Muscarinic receptor agonists

ABSTRACT

where m, p, q, W, Z, Y, X1, X2, R1, R2, R3 and R4 are as defined herein.

RELATED APPLICATION INFORMATION

This application is a continuation of U.S. application Ser. No.15/987,506, filed May 23, 2018, which is a continuation of U.S.application Ser. No. 15/126,935, filed Sep. 16, 2016, now U.S. Pat. No.10,030,035, which is a 371 U.S. national stage of InternationalApplication No.: PCT/GB2015/050807, filed Mar. 19, 2015, which claimspriority from GB Application Serial No.: 1404922.5, filed Mar. 19, 2014.The entire contents of these applications are incorporated herein byreference in their entirety.

This invention relates to a class of novel bridged bicyclic compounds,their salts, pharmaceutical compositions containing them and their usein therapy of the human body. In particular, the invention is directedto a class of compounds, which are agonists of the muscarinic M₁receptor and/or M₄ receptor, and hence are useful in the treatment ofAlzheimer's Disease, schizophrenia, cognitive disorders and otherdiseases mediated by the muscarinic M₁/M₄ receptors, as well as thetreatment or alleviation of pain.

BACKGROUND OF THE INVENTION

Muscarinic acetylcholine receptors (mAChRs) are members of the Gprotein-coupled receptor superfamily which mediate the actions of theneurotransmitter acetylcholine in both the central and peripheralnervous system. Five mAChR subtypes have been cloned, M₁ to M₅. The M₁mAChR is predominantly expressed post-synaptically in the cortex,hippocampus, striatum and thalamus; M₂ mAChRs are located predominantlyin the brainstem and thalamus, though also in the cortex, hippocampusand striatum where they reside on cholinergic synaptic terminals(Langmead et al., 2008 Br J Pharmacol). However, M₂ mAChRs are alsoexpressed peripherally on cardiac tissue (where they mediate the vagalinnervation of the heart) and in smooth muscle and exocrine glands. M₃mAChRs are expressed at relatively low level in the CNS but are widelyexpressed in smooth muscle and glandular tissues such as sweat andsalivary glands (Langmead et al., 2008 Br J Pharmacol).

Muscarinic receptors in the central nervous system, especially the M₁mAChR, play a critical role in mediating higher cognitive processing.Diseases associated with cognitive impairments, such as Alzheimer'sdisease, are accompanied by loss of cholinergic neurons in the basalforebrain (Whitehouse et al., 1982 Science). In schizophrenia, which isalso characterised by cognitive impairments, mAChR density is reduced inthe pre-frontal cortex, hippocampus and caudate putamen of schizophrenicsubjects (Dean et al., 2002 Mol Psychiatry). Furthermore, in animalmodels, blockade or lesion of central cholinergic pathways results inprofound cognitive deficits and non-selective mAChR antagonists havebeen shown to induce psychotomimetic effects in psychiatric patients.Cholinergic replacement therapy has largely been based on the use ofacetylcholinesterase inhibitors to prevent the breakdown of endogenousacetylcholine. These compounds have shown efficacy versus symptomaticcognitive decline in the clinic, but give rise to dose-limiting sideeffects resulting from stimulation of peripheral M₂ and M₃ mAChRsincluding disturbed gastrointestinal motility, bradycardia, nausea andvomiting (www.drugs.com/pro/donepezil.html;www.drugs.com/pro/rivastigmine.html).

Further discovery efforts have targeted the identification of direct M₁mAChR agonists to target increases in cognitive function. Such effortsresulted in the identification of a range of agonists, exemplified bycompounds such as xanomeline, AF267B, sabcomeline, milameline andcevimeline. Many of these compounds have been shown to be highlyeffective in pre-clinical models of cognition in both rodents and/ornon-human primates. Milameline has shown efficacy versusscopolamine-induced deficits in working and spatial memory in rodents;sabcomeline displayed efficacy in a visual object discrimination task inmarmosets and xanomeline reversed mAChR antagonist-induced deficits incognitive performance in a passive avoidance paradigm.

Alzheimer's disease (AD) is the most common neurodegenerative disorder(26.6 million people worldwide in 2006) that affects the elderly,resulting in profound memory loss and cognitive dysfunction. Theaetiology of the disease is complex, but is characterised by twohallmark brain sequelae: aggregates of amyloid plaques, largely composedof amyloid-β peptide (Aβ), and neurofibrillary tangles, formed byhyperphosphorylated tau proteins. The accumulation of Aβ is thought tobe the central feature in the progression of AD and, as such, manyputative therapies for the treatment of AD are currently targetinginhibition of Aβ production. AR is derived from proteolytic cleavage ofthe membrane bound amyloid precursor protein (APP). APP is processed bytwo routes, non-amyloidgenic and amyloidgenic. Cleavage of APP byγ-secretase is common to both pathways, but in the former APP is cleavedby an α-secretase to yield soluble APPα. The cleavage site is within theAβ sequence, thereby precluding its formation. However, in theamyloidgenic route, APP is cleaved by β-secretase to yield soluble APPβand also Aβ. In vitro studies have shown that mAChR agonists can promotethe processing of APP toward the soluble, non-amyloidogenic pathway. Invivo studies showed that the mAChR agonist, AF267B, altered disease-likepathology in the 3×TgAD transgenic mouse, a model of the differentcomponents of Alzheimer's disease (Caccamo et al., 2006 Neuron).Finally, the mAChR agonist cevimeline has been shown to give a small,but significant, reduction in cerebrospinal fluid levels of Aβ inAlzheimer's patients, thus demonstrating potential disease modifyingefficacy (Nitsch et al., 2000 Neurol).

Furthermore, preclinical studies have suggested that mAChR agonistsdisplay an atypical antipsychotic-like profile in a range ofpre-clinical paradigms. The mAChR agonist, xanomeline, reverses a numberof dopamine driven behaviours, including amphetamine induced locomotionin rats, apomorphine induced climbing in mice, dopamine agonist driventurning in unilateral 6-OH-DA lesioned rats and amphetamine inducedmotor unrest in monkeys (without EPS liability). It also has been shownto inhibit A10, but not A9, dopamine cell firing and conditionedavoidance and induces c-fos expression in prefrontal cortex and nucleusaccumbens, but not in striatum in rats. These data are all suggestive ofan atypical antipsychotic-like profile (Mirza et al., 1999 CNS DrugRev). Muscarinic receptors have also been implicated in the neurobiologyof addiction. The reinforcing effects of cocaine and other addictivesubstances are mediated by the mesolimbic dopamine system wherebehavioral and neurochemical studies have shown that the cholinergicmuscarinic receptor subtypes play important roles in regulation ofdopaminergic neurotransmission. For example M(4) (−/−) mice demonstratedsignificantly enhanced reward driven behaviour as result of exposure tococaine (Schmidt et al Psychopharmacology (2011) August; 216(3):367-78).Furthermore xanomeline has been demonstrated to block the effects ofcocaine in these models.

Muscarinic receptors are also involved in the control of movement andpotentially represent novel treatments for movement disorders such asParkinson's disease, ADHD, Huntingdon's disease, tourette's syndrome andother syndromes associated with dopaminergic dysfunction as anunderlying pathogenetic factor driving disease.

Xanomeline, sabcomeline, milameline and cevimeline have all progressedinto various stages of clinical development for the treatment ofAlzheimer's disease and/or schizophrenia. Phase II clinical studies withxanomeline demonstrated its efficacy versus various cognitive symptomdomains, including behavioural disturbances and hallucinationsassociated with Alzheimer's disease (Bodick et al., 1997 Arch Neurol).This compound was also assessed in a small Phase II study ofschizophrenics and gave a significant reduction in positive and negativesymptoms when compared to placebo control (Shekhar et al., 2008 Am JPsych). However, in all clinical studies xanomeline and other relatedmAChR agonists have displayed an unacceptable safety margin with respectto cholinergic side effects, including nausea, gastrointestinal pain,diarrhea, diaphoresis (excessive sweating), hypersalivation (excessivesalivation), syncope and bradycardia.

Muscarinic receptors are involved in central and peripheral pain. Paincan be divided into three different types: acute, inflammatory, andneuropathic. Acute pain serves an important protective function inkeeping the organism safe from stimuli that may produce tissue damagehowever management of post-surgical pain is required.

Inflammatory pain may occur for many reasons including tissue damage,autoimmune response, and pathogen invasion and is triggered by theaction of inflammatory mediators such as neuropeptides andprostaglandins which result in neuronal inflammation and pain.Neuropathic pain is associated with abnormal painful sensations tonon-painful stimuli. Neuropathic pain is associated with a number ofdifferent diseases/traumas such as spinal cord injury, multiplesclerosis, diabetes (diabetic neuropathy), viral infection (such as HIVor Herpes). It is also common in cancer both as a result of the diseaseor a side effect of chemotherapy. Activation of muscarinic receptors hasbeen shown to be analgesic across a number of pain states through theactivation of receptors in the spinal cord and higher pain centres inthe brain. Increasing endogenous levels of acetylcholine throughacetylcholinesterase inhibitors, direct activation of muscarinicreceptors with agonists or allosteric modulators has been shown to haveanalgesic activity. In contrast blockade of muscarinic receptors withantagonists or using knockout mice increases pain sensitivity. Evidencefor the role of the M₁ receptor in pain is reviewed by D. F. Fiorino andM. Garcia-Guzman, 2012.

More recently, a small number of compounds have been identified whichdisplay improved selectivity for the M₁ mAChR subtype over theperipherally expressed mAChR subtypes (Bridges et al., 2008 Bioorg MedChem Lett; Johnson et al., 2010 Bioorg Med Chem Lett; Budzik et al.,2010 ACS Med Chem Lett). Despite increased levels of selectivity versusthe M₃ mAChR subtype, some of these compounds retain significant agonistactivity at both this subtype and the M₂ mAChR subtype. Herein wedescribe a series of compounds which unexpectedly display high levels ofselectivity for the M₁ and/or M₄ mAChR over the M₂ and M₃ receptorsubtypes.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the latencies observed in the passive avoidance test ofExample B.

THE INVENTION

The present invention provides compounds having activity as muscarinicM₁ or M₁ and M₄ receptor agonists. More particularly, the inventionprovides compounds that exhibit selectivity for the M₁, receptorrelative to the M₂ and M₃ receptor subtypes.

Accordingly, in a first embodiment (Embodiment 1.1), the inventionprovides a compound of the formula (1) or formula (1a):

or a salt thereof, wherein:

p is 0, 1 or 2;

q is 0, 1 or 2;

W is C or N;

Z is CH₂, N, O or S;

Y is N, O, S or CH₂;

X¹ and X² are saturated hydrocarbon groups which together contain atotal of five to nine carbon atoms and which link together such that themoiety:

forms a bridged bicyclic ring system;

R¹ can be H, halo, CN, OH, C₁₋₃ alkoxy, NH₂, optionally substituted C₁₋₆alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substitutedC₃₋₆ cycloalkenyl, CH₂—W^(a) where W^(a) is an optionally substituted 5or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring,NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵;SO₃R⁵;

R² can be independently H, halo, CN, OH, C₁₋₃alkoxy, NH₂, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl,optionally substituted C₃₋₆ cycloalkenyl, CH₂—W^(a) where W^(a) is anoptionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl,aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵,OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; or R¹ and R² together form an optionallysubstituted cycloalkyl or heterocycloalkyl ring;

R⁴ can be H, optionally substituted C₁₋₅ alkyl, optionally substitutedC₁₋₅ alkenyl, optionally substituted C₁₋₅ alkynyl, optionallysubstituted C₂₋₆ cycloalkyl, optionally substituted C₂₋₆ cycloalkenyl;

R⁵, R⁶ and R⁷ can be independently H, C₁₋₆ alkyl.

or formula (1a)

or a salt thereof, wherein:

m is 1 or 2

p is 0, 1 or 2;

q is 0, 1 or 2;

W is C or N;

Z is CH₂, N, O or S;

Y is N, O, S or CH₂;

X¹ and X² are saturated hydrocarbon groups which together contain atotal of five to nine carbon atoms and which link together such that themoiety:

forms a bridged bicyclic ring system;

R¹ can be H, halo, CN, OH, C₁₋₃ alkoxy, NH₂, an optionally substitutedC₁₋₆ non-aromatic hydrocarbon group where one or more carbon atoms isoptionally replaced with a heteroatom selected from O, N or S, W^(a) orCH₂—W^(a) where W^(a) is an optionally substituted 5 or 6 memberedcycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵,CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; SO₃R⁵;

R² can be independently H, halo, CN, OH, C₁₋₃ alkoxy, NH₂, an optionallysubstituted C₁₋₆ non-aromatic hydrocarbon group where one or more carbonatoms is optionally replaced with a heteroatom selected from O, N or S,W^(a) or CH₂—W^(a) where W^(a) is an optionally substituted 5 or 6membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶,COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; or R¹and R² or R³ and R² together form an optionally substituted cycloalkylor heterocycloalkyl ring;

R³ can be independently H, OH, an optionally substituted C₁₋₆non-aromatic hydrocarbon group where one or more carbon atoms isoptionally replaced with a heteroatom selected from O, N or S, W^(a) orCH₂—W^(a) where W^(a) is an optionally substituted 5 or 6 memberedcycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; or R³ and R²together form an optionally substituted cycloalkyl or heterocycloalkylring;

R⁴ can be H, optionally substituted C₁₋₅ alkyl, optionally substitutedC₁₋₅ alkenyl, optionally substituted C₁₋₅alkynyl, optionally substitutedC₂₋₆ cycloalkyl, optionally substituted C₂₋₆ cycloalkenyl;

R⁵, R⁶ and R⁷ can be independently H, C₁₋₆ alkyl.

Particular and preferred compounds of the formula (1) or formula (1a)are as defined in the following Embodiments 1.2 to 1.66:

1.2 A compound according to Embodiment 1.1 wherein R¹ is H or a C₁₋₆non-aromatic hydrocarbon group containing 0, 1 or 2 carbon-carbonmultiple bonds, wherein the hydrocarbon group is optionally substitutedwith one to six fluorine atoms and wherein one or two, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidised forms thereof.

1.3 A compound according to either of Embodiments 1.1 and 1.2 wherein R¹is selected from H; C₁₋₆ alkyl; C₂₋₆ alkenyl; C₂₋₆ alkynyl; and C₁₋₆non-aromatic hydrocarbon groups consisting of or containing a C₃₋₆cycloalkyl or C₅₋₆ cycloalkenyl group; each of the said alkyl, alkenyl,alkynyl and non-aromatic hydrocarbon groups being optionally substitutedwith one to six fluorine atoms and wherein one or two, but not all,carbon atoms of each of the alkyl, alkenyl, alkynyl and non-aromatichydrocarbon groups may optionally be replaced by a heteroatom selectedfrom O, N and S and oxidised forms thereof.

1.4 A compound according to Embodiment 1.1 wherein R¹ is a group W^(a)or CH₂—W^(a) where W^(a) is an optionally substituted 5 or 6 memberedcycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, or R¹ and R² arejoined together to form a ring, which may be fused or spirocyclic.

1.5 A compound according to Embodiment 1.1 wherein R¹ is NR⁵R⁶, COOR⁵,CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵ where R⁵, R⁶and R⁷ can be independently H, C₁₋₆ alkyl.

1.6 A compound according to any one of Embodiments 1.1 to 1.5 wherein R¹is selected from:

-   -   H;    -   Halogen;    -   Cyano;    -   OH;    -   C₁₋₃ alkoxy;    -   NH₂;    -   C₁₋₆ alkyl optionally substituted with 1 to 6 fluorine atoms;    -   C₃₋₆ alkyl optionally substituted with 1 heteroatom atom        selected from O, N or S;    -   C₂₋₆ alkenyl;    -   C₂₋₆ alkynyl;    -   C₃₋₆ cycloalkyl;    -   CH₂—C₃₋₆ cycloalkyl;    -   C₅₋₆ cycloalkenyl;    -   CH₂-aryl    -   CH₂-heteroaryl    -   aryl    -   heteroaryl    -   NR⁵R⁶, where R⁵ and R⁶ are independently H, C₁₋₆ alkyl;    -   COOR⁵, where R⁵ is H, C₁₋₆ alkyl;    -   CONR⁵R⁶ where R⁵ and R⁶ are independently H, C₁₋₆ alkyl;    -   NR⁷CONR⁵R⁶, where R⁵, R⁶ and R⁷ are independently H, C₁₋₆ alkyl;    -   NR⁷COOR⁵, where R⁵ and R⁷ are independently H, C₁₋₆ alkyl;    -   OCONR⁵R⁶, where R⁵ and R⁶ are independently H, C₁₋₆ alkyl;    -   SR⁵, where R⁵ is H, C₁₋₆ alkyl;    -   SOR⁵, where R⁵ is H, C₁₋₆ alkyl;    -   SO₂R⁵, where R⁵ is H, C₁₋₆ alkyl;    -   SO₃R⁵, where R⁵ is H, C₁₋₆ alkyl;    -   a spirocycle of formula (CH₂)n where n is 2, 3, 4, 5 or 6.

1.7 A compound according to Embodiment 1.6 wherein R¹ is H or C₁₋₆ alkyloptionally substituted with 1 to 6 fluorine atoms.

1.8 A compound according to Embodiment 1.5 wherein R¹ is H or C₁₋₅alkyl.

1.9 A compound according to any one of Embodiments 1.1 to 1.8 wherein R²is H or a C₁₋₆ non-aromatic hydrocarbon group containing 0, 1 or 2carbon-carbon multiple bonds, wherein the hydrocarbon group isoptionally substituted with one to six fluorine atoms and wherein one ortwo, but not all, carbon atoms of the hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidised formsthereof.

1.10 A compound according to any one of Embodiments 1.1 to 1.9 whereinR² is selected from H; C₁₋₆ alkyl; C₂₋₆ alkenyl; C₂₋₆ alkynyl; and C₁₋₆non-aromatic hydrocarbon groups consisting of or containing aC₃₋₆cycloalkyl or C₅₋₆ cycloalkenyl group; each of the said alkyl,alkenyl, alkynyl and non-aromatic hydrocarbon groups being optionallysubstituted with one to six fluorine atoms and wherein one or two, butnot all, carbon atoms of each of the alkyl, alkenyl, alkynyl andnon-aromatic hydrocarbon groups may optionally be replaced by aheteroatom selected from O, N and S and oxidised forms thereof.

1.11 A compound according to any one of Embodiments 1.1 to 1.8 whereinR² is a group CH₂—W^(a) where W^(a) is an optionally substituted 5 or 6membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, or R¹and R² are joined together to form a ring, which may be fused orspirocyclic.

1.12 A compound according to any one of Embodiments 1.1 to 1.8 whereinR² is NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵,SO₂R⁵ where R⁵, R⁶ and R⁷ can be independently H, C₁₋₆ alkyl.

1.13 A compound according to any one of Embodiments 1.1 to 1.12 whereinR² is selected from:

-   -   H;    -   Halogen;    -   Cyano;    -   OH;    -   C₁₋₃ alkoxy;    -   NH₂;    -   C₁₋₆ alkyl optionally substituted with 1 to 6 fluorine atoms;    -   C₂₋₆ alkenyl;    -   C₂₋₆ alkynyl;    -   C₃₋₆ cycloalkyl;    -   C₅₋₆ cycloalkenyl;    -   CH₂-aryl    -   CH₂-heteroaryl    -   NR⁵R⁶, where R⁵ and R⁶ are independently H, C₁₋₆ alkyl;    -   COOR⁵, where R⁵ is H, C₁₋₆ alkyl;    -   CONR⁵R⁶ where R⁵ and R⁶ are independently H, C₁₋₆ alkyl;    -   NR⁷CONR⁵R⁶, where R⁵, R⁶ and R⁷ are independently H, C₁₋₆ alkyl;    -   NR⁷COOR⁵, where R⁵ and R⁷ are independently H, C₁₋₆ alkyl;    -   OCONR⁵R⁶, where R⁵ and R⁶ are independently H, C₁₋₆ alkyl;    -   SR⁵, where R⁵ is H, C₁₋₆ alkyl;    -   SOR⁵, where R⁵ is H, C₁₋₆ alkyl;    -   SO₂R⁵, where R⁵ is H, C₁₋₆ alkyl;    -   SO₃R⁵, where R⁵ is H, C₁₋₆ alkyl.

1.13 A compound according to Embodiment 1.12 wherein R² is H or C₁₋₆alkyl optionally substituted with 1 to 6 fluorine atoms.

1.14 A compound according to Embodiment 1.13 wherein R² is H or C₁₋₆alkyl.

1.15 A compound according to any one of Embodiments 1.1 to 1.14 whereinR¹ and R² are selected from hydrogen and C₁₋₆ alkyl.

1.16 A compound according to Embodiments 1.15 wherein R¹ and R² areindependently H, methyl, ethyl, propyl, isopropyl or benzyl.

1.17 A compound according to Embodiment 1.1 wherein R¹ and R² togetheror the R³ and R² together form an optionally substituted cycloalkyl orheterocycloalkyl ring. The ring can replace the R³ group atom on thenitrogen. The ring may be fused or spirocyclic.

1.18 A compound according to Embodiment 1.17 wherein R¹ and R² togetherform a cycloalkyl ring optionally incorporating a maximum of 2heteroatoms selected from O, S or N, and optionally substituted by amaximum of 6 atoms of F.

1.19 A compound according to Embodiment 1.1 wherein R³ is H, OH or aC₁₋₆ non-aromatic hydrocarbon group containing 0, 1 or 2 carbon-carbonmultiple bonds, wherein the hydrocarbon group is optionally substitutedwith one to six fluorine atoms and wherein one or two, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidised forms thereof.

1.20 A compound according to either of Embodiment 1, 19 wherein R³ isselected from H; OH, C₁₋₆ alkyl; C₂₋₅ alkenyl; C₂₋₆ alkynyl; and C₁₋₆non-aromatic hydrocarbon groups consisting of or containing aC₃₋₆cycloalkyl or C₅₋₆ cycloalkenyl group; each of the said alkyl,alkenyl, alkynyl and non-aromatic hydrocarbon groups being optionallysubstituted with one to six fluorine atoms and wherein one or two, butnot all, carbon atoms of each of the alkyl, alkenyl, alkynyl andnon-aromatic hydrocarbon groups may optionally be replaced by aheteroatom selected from O, N and S and oxidised forms thereof.

1.21 A compound according to Embodiment 1.19 wherein R³ is a group W^(a)or CH₂—W^(a) where W^(a) is an optionally substituted 5 or 6 memberedcycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, or R¹ and R₂ arejoined together to form a ring, which may be fused or spirocyclic.

1.22 A compound according to any one of Embodiments 1.19 to 1.21 whereinR³ is selected from:

-   -   H;    -   OH    -   C₁₋₆ alkyl optionally substituted with 1 to 6 fluorine atoms;    -   C₃₋₆ alkyl optionally substituted with 1 heteroatom atom        selected from O, N or S;    -   C₂₋₆ alkenyl;    -   C₂₋₆ alkynyl;    -   C₃₋₆ cycloalkyl;    -   CH₂—C₃₋₆ cycloalkyl;    -   C₅₋₆ cycloalkenyl;    -   CH₂-aryl    -   CH₂-heteroaryl    -   aryl    -   heteroaryl

1.23 A compound according to Embodiment 1.22 wherein R³ is H or C₁₋₆alkyl optionally substituted with 1 to 6 fluorine atoms.

1.24 A compound according to Embodiment 1.5 wherein R³ is H or C₁₋₅alkyl.

1.25 A compound according to any one of Embodiments 1.1 to 1.24 whereinZ is CH₂, N, O or S.

1.26 A compound according to Embodiment 1.25 wherein Z is CH₂N or O.

1.27 A compound according to Embodiment 1.25 wherein Z is CH₂.

1.28 A compound according to Embodiment 1.25 wherein Z is N.

1.29 A compound according to Embodiment 1.25 wherein Z is O. When Z isO, R³ can be specified as being H. Alternatively when Z is O, m can bespecified as being 2. Alternatively when Z is O, either R³ is H or m is2.

1.30 A compound according to any one of Embodiments 1.1 to 1.29 whereinR⁴ is H or an acyclic C₁₋₄ hydrocarbon group optionally substituted withone or more fluorine atoms.

1.31 A compound according to Embodiment 1.30 wherein R⁴ is H or anacyclic C₁₋₃ hydrocarbon group optionally substituted with one or morefluorine atoms.

1.32 A compound according to Embodiment 1.31 wherein R⁴ is H or a C₁₋₃alkyl group or a C₁₋₂ alkynyl group.

1.33 A compound according to Embodiment 1.32 wherein R⁴ is selected fromH, methyl, fluoromethyl, ethyl, ethynyl and 1-propynyl.

1.34 A compound according to Embodiment 1.33 wherein R⁴ is methyl.

1.35 A compound according to any one of Embodiments 1.1 to 1.34 whereinp is 0 or 1.

1.36 A compound according to Embodiment 1.35 wherein p is 0.

1.37 A compound according to Embodiment 1.35 wherein q is 0 or 1.

1.38 A compound according to any one of Embodiments 1.1 to 1.37 whereinm is 0.

1.39 A compound according to any one of Embodiments 1.1 to 1.37 whereinm is 1.

1.40 A compound according to any one of Embodiments 1.1 to 1.39 whereinY is N, O, or CH₂.

1.41 A compound according to Embodiment 1.40 wherein Y is N.

1.42 A compound according to Embodiment 1.40 wherein Y is O.

1.43 A compound according to any one of Embodiments 1.1 to 1.40 whereinW is C.

1.44 A compound according to Embodiments 1.1 to 1.43 wherein the bridgedbicyclic ring system is an azabicyclo-heptane, azabicyclo-octane orazabicyclo-nonane ring system.

1.45 A compound according to Embodiment 1.44 wherein the bridgedbicyclic ring system is selected from ring systems BA to BH below whichmay be substituted with 0-2 optional fluorine atoms:

1.46 A compound according to Embodiment 1.45 wherein q is 0 or 1.

1.47 A compound according to any one of Embodiments 1.1 to 1.46 whereinR⁵ is H or C₁₋₆ alkyl.

1.48 A compound according to Embodiment 1.47 wherein R⁵ is H.

1.49 A compound according to Embodiment 1.47 wherein R⁵ is C₁₋₃ alkyl.

1.50 A compound according to any one of Embodiments 1.1 to 1.49 whereinR⁶ is H or C₁₋₅ alkyl.

1.51 A compound according to Embodiment 1.50 wherein R⁶ is H.

1.52 A compound according to Embodiment 1.50 wherein R⁶ is C₁₋₃ alkyl.

1.53 A compound according to any one of Embodiments 1.1 to 1.52 whereinR⁷ is H or C₁₋₅ alkyl.

1.54 A compound according to Embodiment 1.53 wherein R⁷ is H.

1.55 A compound according to Embodiment 1.53 wherein R⁷ is C₁₋₃ alkyl.

1.56 A compound according to Embodiment 1.1 having the formula (2) orformula (2a):

wherein n is 1 or 2;

A and B are linked together to form a carbon bridge of 1-3 atoms where nis 1, or 1-2 carbon atoms where n is 2 and p, q, W, Z, Y, R¹, R² and R⁴are as defined in any one of Embodiments 1.1 to 1.43; or

wherein n is 1 or 2;

A and B are linked together to form a carbon bridge of 1-3 atoms where nis 1, or 1-2 carbon atoms where n is 2 and m, p, q, W, Z, Y, R¹, R², R³and R⁴ are as defined in any one of Embodiments 1.1 to 1.43.

1.57 A compound according to Embodiment 1.1 having the formula (3) orformula (3a):

wherein r is 1, 2 or 3 and each of s, t u and v is 0 or 1, provided thatthe total of r, s, t, u and v is 3, 4 or 5, and p, q, W, Z, Y, R¹, R²and R⁴ are as defined in any one of Embodiments 1.1 to 1.43; or

wherein r is 1, 2 or 3 and each of s, t u and v is 0 or 1, provided thatthe total of r, s, t, u and v is 3, 4 or 5, and m, p, q, W, Z, Y, R¹,R², R³ and R⁴ are as defined in any one of Embodiments 1.1 to 1.43.

1.58 A compound according to Embodiment 1.1 having the formula (4) orformula (4a):

wherein R¹, W, Z, Y and R⁴ are as defined in any one of Embodiments 1.1to 1.43; or

wherein m, R¹, R², W, Z, Y and R⁴ are as defined in any one ofEmbodiments 1.1 to 1.43.

1.59 A compound according to any one of Embodiments 1.56 to 1.58 whereinZ is CH₂N or O.

1.60 A compound according to any one of Embodiments 1.56 to 1.59 whereinR⁴ is selected from H, methyl, ethyl, ethynyl and 1-propynyl.

1.61 A compound according to Embodiment 1.60 wherein R⁴ is selected fromH or methyl.

1.62 A compound according to Embodiment 1.1 which is as defined in anyone of Examples 1-1 to 9-2.

1.63 A compound according to any one of Embodiments 1.1 to 1.61 having amolecular weight of less than 550, for example less than 500, or lessthan 450.

1.64 A compound according to any one of Embodiments 1.1 to 1.63 which isin the form of a salt.

1.65 A compound according to Embodiment 1.64 wherein the salt is an acidaddition salt.

1.66 A compound according to Embodiment 1.64 or Embodiment 1.65 whereinthe salt is a pharmaceutically acceptable salt.

Definitions

In this application, the following definitions apply, unless indicatedotherwise.

The term “treatment”, in relation to the uses of the compounds of theformula (1) or formula (1a), is used to describe any form ofintervention where a compound is administered to a subject sufferingfrom, or at risk of suffering from, or potentially at risk of sufferingfrom the disease or disorder in question. Thus, the term “treatment”covers both preventative (prophylactic) treatment and treatment wheremeasurable or detectable symptoms of the disease or disorder are beingdisplayed.

The term “effective therapeutic amount” as used herein (for example inrelation to methods of treatment of a disease or condition) refers to anamount of the compound which is effective to produce a desiredtherapeutic effect. For example, if the condition is pain, then theeffective therapeutic amount is an amount sufficient to provide adesired level of pain relief. The desired level of pain relief may be,for example, complete removal of the pain or a reduction in the severityof the pain.

The term “non-aromatic hydrocarbon group” (as in “C₁₋₅ non-aromatichydrocarbon group” or “acyclic C₁₋₅ non-aromatic hydrocarbon group”refers to a group consisting of carbon and hydrogen atoms and whichcontains no aromatic rings. The hydrocarbon group may be fully saturatedor may contain one or more carbon-carbon double bonds or carbon-carbontriple bonds, or mixtures of double and triple bonds. The hydrocarbongroup may be a straight chain or branched chain group or may consist ofor contain a cyclic group. Thus the term non-aromatic hydrocarbonincludes alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenyl alkyl CH₂-cycloalkyl and so on.

The terms “alkyl”, “alkenyl”, “alkynyl”, “cycloalkyl” and “cycloalkenyl”are used in their conventional sense (e.g. as defined in the IUPAC GoldBook) unless indicated otherwise.

The term “cycloalkyl” as used herein, where the specified number ofcarbon atoms permits, includes both monocyclic cycloalkyl groups such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, andbicyclic and tricyclic groups. Bicyclic cycloalkyl groups includebridged ring systems such as bicycloheptane, bicyclooctane andadamantane.

In the definitions of R¹, R², R³ and R⁴ above, where stated, one or twobut not all, carbon atoms of the non-aromatic hydrocarbon group mayoptionally be replaced by a heteroatom selected from O, N and S andoxidised forms thereof. It will be appreciated that when a carbon atomis replaced by a heteroatom, the lower valencies of the heteroatomscompared to carbon means that fewer atoms will be bonded to theheteroatoms than would have been bonded to the carbon atom that has beenreplaced. Thus, for example, replacement of a carbon atom (valency offour) in a CH₂ group by oxygen (valency of two) will mean that theresulting molecule will contain two less hydrogen atoms and replacementof a carbon atom (valency of four) in a CH₂ group by nitrogen (valencyof three) will mean that the resulting molecule will contain one lesshydrogen atom.

Examples of a heteroatom replacements for carbon atoms includereplacement of a carbon atom in a —CH₂—CH₂—CH₂— chain with oxygen orsulfur to give an ether —CH₂—O—CH₂— or thioether —CH₂—S—CH₂—,replacement of a carbon atom in a group CH₂—C≡C—H with nitrogen to givea nitrile (cyano) group CH₂—C≡N, replacement of a carbon atom in a group—CH₂—CH₂—CH₂— with C═O to give a ketone —CH₂—C(O)—CH₂—, replacement of acarbon atom in a group —CH₂—CH₂—CH₂— with S═O or SO₂ to give a sulfoxide—CH₂—S(O)—CH₂— or sulfone —CH₂—S(O)₂—CH₂—, replacement of a carbon atomin a —CH₂—CH₂—CH₂-chain with C(O)NH to give an amide —CH₂—CH₂—C(O)—NH—,replacement of a carbon atom in a —CH₂—CH₂—CH₂— chain with nitrogen togive an amine —CH₂—NH—CH₂—, and replacement of a carbon atom in a—CH₂—CH₂—CH₂— chain with C(O)O to give an ester (or carboxylic acid)—CH₂—CH₂—C(O)—O—. In each such replacement, at least one carbon atom ofthe hydrocarbon group must remain.

Salts

Many compounds of the formula (1) or formula (1a) can exist in the formof salts, for example acid addition salts or, in certain cases salts oforganic and inorganic bases such as carboxylate, sulfonate and phosphatesalts. All such salts are within the scope of this invention, andreferences to compounds of the formula (1) or formula (1a) include thesalt forms of the compounds as defined in Embodiments 1.64 to 1.66.

The salts are typically acid addition salts.

The salts of the present invention can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods such as methods described in Pharmaceutical Salts: Properties,Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth(Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.Generally, such salts can be prepared by reacting the free acid or baseforms of these compounds with the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally, nonaqueousmedia such as ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are used.

Acid addition salts (as defined in Embodiment 1.65) may be formed with awide variety of acids, both inorganic and organic. Examples of acidaddition salts falling within Embodiment 1.65 include mono- or di-saltsformed with an acid selected from the group consisting of acetic,2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic),L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric,ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic,fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic(e.g. D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric,glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric,hydriodic), isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic),lactobionic, maleic, malic, (−)-L-malic, malonic, (±)-DL-mandelic,methanesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic,1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic,palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic,salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric,tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic andvaleric acids, as well as acylated amino acids and cation exchangeresins.

Where the compounds of the formula (1) or formula (1a) contain an aminefunction, these may form quaternary ammonium salts, for example byreaction with an alkylating agent according to methods well known to theskilled person. Such quaternary ammonium compounds are within the scopeof formula (1) or formula (1a).

The compounds of the invention may exist as mono- or di-salts dependingupon the pKa of the acid from which the salt is formed.

The salt forms of the compounds of the invention are typicallypharmaceutically acceptable salts, and examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, saltsthat are not pharmaceutically acceptable may also be prepared asintermediate forms which may then be converted into pharmaceuticallyacceptable salts. Such non-pharmaceutically acceptable salts forms,which may be useful, for example, in the purification or separation ofthe compounds of the invention, also form part of the invention.

Stereoisomers

Stereoisomers are isomeric molecules that have the same molecularformula and sequence of bonded atoms but which differ only in thethree-dimensional orientations of their atoms in space. Thestereoisomers can be, for example, geometric isomers or optical isomers.

Geometric Isomers

With geometric isomers, the isomerism is due to the differentorientations of an atom or group about a double bond, as in cis andtrans (Z and E) isomerism about a carbon-carbon double bond, or cis andtrans isomers about an amide bond, or syn and anti isomerism about acarbon nitrogen double bond (e.g. in an oxime), or rotational isomerismabout a bond where there is restricted rotation, or cis and transisomerism about a ring such as a cycloalkane ring.

Accordingly, in another embodiment (Embodiment 1.67), the inventionprovides a geometric isomer of a compound according to any one ofEmbodiments 1.1 to 1.66.

Optical Isomers

Where compounds of the formula contain one or more chiral centres, andcan exist in the form of two or more optical isomers, references to thecompounds include all optical isomeric forms thereof (e.g. enantiomers,epimers and diastereoisomers), either as individual optical isomers, ormixtures (e.g. racemic mixtures) or two or more optical isomers, unlessthe context requires otherwise.

Accordingly, in another embodiment (Embodiment 1.68) the inventionprovides a compound according to any one of Embodiments 1.1 to 1.67which contains a chiral centre.

The optical isomers may be characterised and identified by their opticalactivity (i.e. as + and − isomers, or d and/isomers) or they may becharacterised in terms of their absolute stereochemistry using the “Rand S” nomenclature developed by Cahn, Ingold and Prelog, see AdvancedOrganic Chemistry by Jerry March, 4^(th) Edition, John Wiley & Sons, NewYork, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew.Chem. Int. Ed. Engl., 1966, 5, 385-415. Optical isomers can be separatedby a number of techniques including chiral chromatography(chromatography on a chiral support) and such techniques are well knownto the person skilled in the art. As an alternative to chiralchromatography, optical isomers can be separated by formingdiastereoisomeric salts with chiral acids such as (+)-tartaric acid,(−)-pyroglutamic acid, (−)-di-toluoyl-L-tartaric acid, (+)-mandelicacid, (−)-malic acid, and (−)-camphorsulphonic, separating thediastereoisomers by preferential crystallisation, and then dissociatingthe salts to give the individual enantiomer of the free base.

Where compounds of the invention exist as two or more optical isomericforms, one enantiomer in a pair of enantiomers may exhibit advantagesover the other enantiomer, for example, in terms of biological activity.Thus, in certain circumstances, it may be desirable to use as atherapeutic agent only one of a pair of enantiomers, or only one of aplurality of diastereoisomers.

Accordingly, in another embodiment (Embodiment 1.69), the inventionprovides compositions containing a compound according to Embodiment 1.68having one or more chiral centres, wherein at least 55% (e.g. at least60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of Embodiment1.65 is present as a single optical isomer (e.g. enantiomer ordiastereoisomer).

In one general embodiment (Embodiment 1.70), 99% or more (e.g.substantially all) of the total amount of the compound (or compound foruse) of Embodiment 1.68 is present as a single optical isomer.

For example, in one embodiment (Embodiment 1.71) the compound is presentas a single enantiomer.

In another embodiment (Embodiment 1.72), the compound is present as asingle diastereoisomer.

The invention also provides mixtures of optical isomers, which may beracemic or non-racemic. Thus, the invention provides:

1.73 A compound according to Embodiment 1.68 which is in the form of aracemic mixture of optical isomers.

1.74 A compound according to Embodiment 1.68 which is in the form of anon-racemic mixture of optical isomers.

Isotopes

The compounds of the invention as defined in any one of Embodiments 1.1to 1.74 may contain one or more isotopic substitutions, and a referenceto a particular element includes within its scope all isotopes of theelement. For example, a reference to hydrogen includes within its scope¹H, ²H (D), and ³H (T). Similarly, references to carbon and oxygeninclude within their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and¹⁸O.

In an analogous manner, a reference to a particular functional groupalso includes within its scope isotopic variations, unless the contextindicates otherwise. For example, a reference to an alkyl group such asan ethyl group also covers variations in which one or more of thehydrogen atoms in the group is in the form of a deuterium or tritiumisotope, e.g. as in an ethyl group in which all five hydrogen atoms arein the deuterium isotopic form (a perdeuteroethyl group).

The isotopes may be radioactive or non-radioactive. In one embodiment ofthe invention (Embodiment 1.75), the compound of any one of Embodiments1.1 to 1.74 contains no radioactive isotopes. Such compounds arepreferred for therapeutic use.

In another embodiment (Embodiment 1.76), however, the compound of anyone of Embodiments 1.1 to 1.74 may contain one or more radioisotopes.Compounds containing such radioisotopes may be useful in a diagnosticcontext.

Solvates

Compounds of the formula (1) or formula (1a) as defined in any one ofEmbodiments 1.1 to 1.76 may form solvates. Preferred solvates aresolvates formed by the incorporation into the solid state structure(e.g. crystal structure) of the compounds of the invention of moleculesof a non-toxic pharmaceutically acceptable solvent (referred to below asthe solvating solvent). Examples of such solvents include water,alcohols (such as ethanol, isopropanol and butanol) anddimethylsulfoxide. Solvates can be prepared by recrystallising thecompounds of the invention with a solvent or mixture of solventscontaining the solvating solvent. Whether or not a solvate has beenformed in any given instance can be determined by subjecting crystals ofthe compound to analysis using well known and standard techniques suchas thermogravimetric analysis (TGE), differential scanning calorimetry(DSC) and X-ray crystallography. The solvates can be stoichiometric ornon-stoichiometric solvates. Particularly preferred solvates arehydrates, and examples of hydrates include hemihydrates, monohydratesand dihydrates.

Accordingly, in further embodiments 1.77 and 1.78, the inventionprovides:

1.77 A compound according to any one of Embodiments 1.1 to 1.76 in theform of a solvate.

1.78 A compound according to Embodiment 1.77 wherein the solvate is ahydrate.

For a more detailed discussion of solvates and the methods used to makeand characterise them, see Bryn et al., Solid-State Chemistry of Drugs,Second Edition, published by SSCI, Inc of West Lafayette, Ind., USA,1999, ISBN 0-967-06710-3.

Alternatively, rather than existing as a hydrate, the compound of theinvention may be anhydrous. Therefore, in another embodiment (Embodiment1.79), the invention provides a compound as defined in any one ofEmbodiments 1.1 to 1.76 in an anhydrous form (e.g. anhydrous crystallineform).

Crystalline and Amorphous Forms

The compounds of any one of Embodiments 1.1 to 1.79 may exist in acrystalline or non-crystalline (e.g. amorphous) state. Whether or not acompound exists in a crystalline state can readily be determined bystandard techniques such as X-ray powder diffraction (XRPD). Crystalsand their crystal structures can be characterised using a number oftechniques including single crystal X-ray crystallography, X-ray powderdiffraction (XRPD), differential scanning calorimetry (DSC) and infrared spectroscopy, e.g. Fourier Transform infra-red spectroscopy (FTIR).The behaviour of the crystals under conditions of varying humidity canbe analysed by gravimetric vapour sorption studies and also by XRPD.Determination of the crystal structure of a compound can be performed byX-ray crystallography which can be carried out according to conventionalmethods such as those described herein and as described in Fundamentalsof Crystallography, C. Giacovazzo, H. L. Monaco, D. Viterbo, F.Scordari, G. Gilli, G. Zanotti and M. Catti, (International Union ofCrystallography/Oxford University Press, 1992 ISBN 0-19-855578-4 (p/b),0-19-85579-2 (h/b)). This technique involves the analysis andinterpretation of the X-ray diffraction of single crystal. In anamorphous solid, the three dimensional structure that normally exists ina crystalline form does not exist and the positions of the moleculesrelative to one another in the amorphous form are essentially random,see for example Hancock et al. J. Pharm. Sci. (1997), 86, 1).

Accordingly, in further embodiments, the invention provides:

1.80 A compound according to any one of Embodiments 1.1 to 1.79 in acrystalline form.

1.781 A compound according to any one of Embodiments 1.1 to 1.79 whichis:

(a) from 50% to 100% crystalline, and more particularly is at least 50%crystalline, or at least 60% crystalline, or at least 70% crystalline,or at least 80% crystalline, or at least 90% crystalline, or at least95% crystalline, or at least 98% crystalline, or at least 99%crystalline, or at least 99.5% crystalline, or at least 99.9%crystalline, for example 100% crystalline.

1.82 A compound according to any one of Embodiments 1.1 to 1.79 which isin an amorphous form.

Prodrugs

The compounds of the formula (1) or formula (1a) as defined in any oneof Embodiments 1.1 to 1.76 may be presented in the form of a pro-drug.By “prodrugs” is meant for example any compound that is converted invivo into a biologically active compound of the formula (1) or formula(1a), as defined in any one of Embodiments 1.1 to 1.76.

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). Duringmetabolism, the ester group (—C(═O)OR) is cleaved to yield the activedrug. Such esters may be formed by esterification, for example, of anyhydroxyl groups present in the parent compound with, where appropriate,prior protection of any other reactive groups present in the parentcompound, followed by deprotection if required.

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). Forexample, the prodrug may be a sugar derivative or other glycosideconjugate, or may be an amino acid ester derivative.

Accordingly, in another embodiment (Embodiment 1.83), the inventionprovides a pro-drug of a compound as defined in any one of Embodiments1.1 to 1.76 wherein the compound contains a functional group which isconvertible under physiological conditions to form a hydroxyl group oramino group.

Complexes and Clathrates

Also encompassed by formula (1) or formula (1a) in Embodiments 1.1 to1.83 are complexes (e.g. inclusion complexes or clathrates withcompounds such as cyclodextrins, or complexes with metals) of thecompounds of Embodiments 1.1 to 1.83.

Accordingly, in another embodiment (Embodiment 1.84), the inventionprovides a compound according to any one of Embodiments 1.1 to 1.83 inthe form of a complex or clathrate.

Biological Activity and Therapeutic Uses

The compounds of the present invention have activity as muscarinic M₁receptor agonists. The muscarinic activity of the compounds can bedetermined using the Phospho-ERK1/2 assay described in Example A below.

A significant advantage of compounds of the invention is that they arehighly selective for the M₁ receptor relative to the M₂ and M₃ receptorsubtypes. Compounds of the invention are neither agonists norantagonists of the M₂ and M₃ receptor subtypes. For example, whereascompounds of the invention typically have pEC₅₀ values of at least 6(preferably at least 6.5) and E_(max) values of greater than 80(preferably greater than 95) against the M₁ receptor in the functionalassay described in Example A, they may have pEC₅₀ values of less than 5and E_(max) values of less than 20% when tested against the M₂ and M₃subtypes in the functional assay of Example A.

Some compounds of the invention have activity at both the M₁ and M₄receptors.

Accordingly, in Embodiments 2.1 to 2.9, the invention provides:

2.1 A compound according to any one of Embodiments 1.1 to 1.84 for usein medicine.

2.2 A compound according to any one of Embodiments 1.1 to 1.84 for useas a muscarinic M₁ or M₁ and M₄ receptor agonist.

2.3 A compound according to any one of Embodiments 1.1 to 1.84 which isa muscarinic M₁ receptor agonist having a pEC₅₀ greater than 6.9 and anE_(max) of at least 80 against the M₁ receptor in the assay of Example Aherein or an assay substantially similar thereto.

2.4 A compound according to Embodiment 2.3 which is a muscarinic M₁receptor agonist having a pEC₅₀ greater than 7.0.

2.5 A compound according to Embodiment 2.3 or Embodiment 2.4 having anE_(max) of at least 90 against the M₁ receptor.

2.6 A compound according to any one of Embodiments 1.1 to 1.84 which isa muscarinic M₁ and M₄ receptor agonist having a pEC₅₀ in the range from6.0 to 8.7 and an E_(max) of at least 60 against the M₄ receptor in theassay of Example A herein or an assay substantially similar thereto.

2.7 A compound according to any one of Embodiments 1.1 to 1.84 which isa muscarinic M₁ and M₄ receptor agonist having a pEC₅₀ in the range from6.0 to 8.1 and an E_(max) of at least 90 against the M₄ receptor in theassay of Example A herein or an assay substantially similar thereto.

2.8 A compound according to Embodiment 2.6 which is a muscarinic M₄receptor agonist having a pEC₅₀ in the range from 7.5 to 8.7.

2.9 A compound according to Embodiment 2.7 which is a muscarinic M₄receptor agonist having a pEC₅₀ in the range from 6.5 to 7.5.

2.10 A compound according to Embodiment 2.6 or Embodiment 2.8 having anE_(max) of at least 75 against the M₄ receptor.

2.11 A compound according to Embodiment 2.7 or Embodiment 2.9 having anE_(max) of at least 95 against the M₄ receptor.

2.12 A compound according to any one of Embodiments 2.3 to 2.11 which isselective for the M₁ and M₄ receptor compared to the muscarinic M₂ andM₃ receptors.

2.13 A compound according to Embodiment 2.12 which is selective for theM₁ receptor compared to the muscarinic M₂ and M₃ receptors.

2.14 A compound according to any one of Embodiments 2.3 to 2.5 which isselective for the M₁ receptor compared to the muscarinic M₂, M₃ and M₄receptors.

2.15 A compound according to any one of Embodiments 2.3 to 2.14 whichhas a pEC₅₀ of less than 5 and an E_(max) of less than 50 against themuscarinic M₂ and M₃ receptor subtypes.

2.16 A compound according to Embodiment 2.15 which has a pEC₅₀ of lessthan 4.5 and/or an E_(max) of less than 30 against the muscarinic M₂ andM₃ receptor subtypes.

2.17 A compound according to any one of Embodiments 1.1 to 1.84 andEmbodiments 2.3 to 2.16 for use in the treatment of a disease orcondition mediated by the muscarinic M₁ receptor.

By virtue of their muscarinic M₁ or M₁ and M₄ receptor agonist activity,compounds of the invention can be used in the treatment of Alzheimer'sdisease, schizophrenia and other psychotic disorders, cognitivedisorders and other diseases mediated by the muscarinic M₁ or M₁ and M₄receptor, and can also be used in the treatment of various types ofpain.

Accordingly, in Embodiments 2.16 to 2.39, the invention provides:

2.18 A compound according to any one of Embodiments 1.1 to 1.84 for usein the treatment of a cognitive disorder or psychotic disorder.

2.19 A compound for use in according to Embodiment 2.18 wherein thecognitive disorder or psychotic disorder comprises, arises from or isassociated with a condition selected from cognitive impairment, MildCognitive Impairment, frontotemporal dementia, vascular dementia,dementia with Lewy bodies, presenile dementia, senile dementia,Friederich's ataxia, Down's syndrome, Huntington's chorea, hyperkinesia,mania, Tourette's syndrome, Alzheimer's disease, progressivesupranuclear palsy, impairment of cognitive functions includingattention, orientation, learning disorders, memory (i.e. memorydisorders, amnesia, amnesic disorders, transient global amnesia syndromeand age-associated memory impairment) and language function; cognitiveimpairment as a result of stroke, Huntington's disease, Pick disease,Aids-related dementia or other dementia states such as multi-infarctdementia, alcoholic dementia, hypothyroidism-related dementia, anddementia associated to other degenerative disorders such as cerebellaratrophy and amyotropic lateral sclerosis; other acute or sub-acuteconditions that may cause cognitive decline such as delirium ordepression (pseudodementia states) trauma, head trauma, age relatedcognitive decline, stroke, neurodegeneration, drug-induced states,neurotoxic agents, age related cognitive impairment, autism relatedcognitive impairment, Down's syndrome, cognitive deficit related topsychosis, and post-electroconvulsive treatment related cognitivedisorders; cognitive disorders due to drug abuse or drug withdrawalincluding nicotine, cannabis, amphetamine, cocaine, Attention DeficitHyperactivity Disorder (ADHD) and dyskinetic disorders such asParkinson's disease, neuroleptic-induced parkinsonism, and tardivedyskinesias, schizophrenia, schizophreniform diseases, psychoticdepression, mania, acute mania, paranoid, hallucinogenic and delusionaldisorders, personality disorders, obsessive compulsive disorders,schizotypal disorders, delusional disorders, psychosis due tomalignancy, metabolic disorder, endocrine disease or narcolepsy,psychosis due to drug abuse or drug withdrawal, bipolar disorders andschizo-affective disorder.

2.20 A compound according to any one of Embodiments 1.1 to 1.84 for usein the treatment of Alzheimer's disease.

2.21 A compound according to any one of Embodiments 1.1 to 1.84 for usein the treatment of Schizophrenia.

2.22 A method of treatment of a cognitive disorder in a subject (e.g. amammalian patient such as a human, e.g. a human in need of suchtreatment), which method comprises the administration of atherapeutically effective dose of a compound according to any one ofEmbodiments 1.1 to 1.84.

2.23 A method according to Embodiment 2.22 wherein the cognitivedisorder comprises, arises from or is associated with a condition asdefined in Embodiment 2.17.

2.24 A method according to Embodiment 2.23 wherein the cognitivedisorder arises from or is associated with Alzheimer's disease.

2.25 A method according to Embodiment 2.23 wherein the cognitivedisorder is Schizophrenia.

2.26 The use of a compound according to any one of Embodiments 1.1 to1.84 for the manufacture of a medicament for the treatment of acognitive disorder.

2.27 The use according to Embodiment 2.26 wherein the cognitive disordercomprises, arises from or is associated with a condition as defined inEmbodiment 2.19.

2.28 The use according to Embodiment 2.27 wherein the cognitive disorderarises from or is associated with Alzheimer's disease.

2.29 The use according to Embodiment 2.28 wherein the cognitive disorderis Schizophrenia.

2.30 A compound according to any one of Embodiments 1.1 to 1.84 for thetreatment or lessening the severity of acute, chronic, neuropathic, orinflammatory pain, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpetic neuralgia, general neuralgias, visceral pain,osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, or cancer pain.

2.31 A method of treatment or lessening the severity of acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, or cancer pain, which method comprises theadministration of a therapeutically effective dose of a compoundaccording to any one of Embodiments 1.1 to 1.84.

2.32 A compound according to any one of Embodiments 1.1 to 1.84 for thetreatment of peripheral disorders such as reduction of intra ocularpressure in Glaucoma and treatment of dry eyes and dry mouth includingSjogren's Syndrome.

2.33 A method of treatment of peripheral disorders such as reduction ofintra ocular pressure in Glaucoma and treatment of dry eyes and drymouth including Sjogren's Syndrome, which method comprises theadministration of a therapeutically effective dose of a compoundaccording to any one of Embodiments 1.1 to 1.84.

2.34 The use of a compound according to any one of Embodiments 1.1 to1.84 for the manufacture of a medicament for the treatment or lesseningthe severity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, visceral pain, osteoarthritis pain,postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica,back pain, head or neck pain, severe or intractable pain, nociceptivepain, breakthrough pain, postsurgical pain, or cancer pain or for thetreatment of peripheral disorders such as reduction of intra ocularpressure in Glaucoma and treatment of dry eyes and dry mouth includingSjogren's Syndrome.

2.35 The use of a compound according to any one of Embodiments 1.1 to1.84 for the use in the treatment of skin lesions for example due topemphigus vulgaris, dermatitis herpetiformis, pemphigoid and otherblistering skin conditions.

2.36 The use of a compound according to any one of Embodiments 1.1 to1.84 for the use in treating, preventing, ameliorating or reversingconditions associated with altered gastro-intestinal function andmotility such as functional dyspepsia, irritable bowel syndrome,gastroesophageal acid reflux (GER) and esophageal dysmotility, symptomsof gastroparesis and chronic diarrhea.

2.37 The use of a compound according to any one of Embodiments 1.1 to1.84 for the use in the treatment of olfactory dysfunction such asBosma-Henkin-Christiansen syndrome, chemical poisoning (e.g. seleniumand silver), hypopituitarism, Kallmann Syndrome, skull fractures, tumourtherapy and underactive thyroid gland.

2.38 The use of a compound according to any one of Embodiments 1.1 to1.84 for the treatment of addiction.

2.39 The use of a compound according to any one of Embodiments 1.1 to1.84 for the treatment of movement disorders such as Parkinson'sdisease, ADHD, Huntingdon's disease, tourette's syndrome and othersyndromes associated with dopaminergic dysfunction as an underlyingpathogenetic factor driving disease.

Methods for the Preparation of Compounds of the Formula (1) or Formula(1a)

Compounds of the formula (1) or formula (1a) can be prepared inaccordance with synthetic methods well known to the skilled person andas described herein.

Accordingly, in another embodiment (Embodiment 3.1), the inventionprovides a process for the preparation of a compound as defined in anyone of Embodiments 1.1 to 1.84, which process comprises:

(A) the reaction of a compound of the formula (10)

with a compound of the formula (11):

under reductive amination conditions; wherein R¹, R², R³, R⁴, X¹, X², W,Y, Z, m, p and q are as defined in any one of Embodiments 1.1 to 1.84;or

(B) the reaction of a compound of the formula (12):

with a compound of the formula Cl—C(═O)—CH₂—R⁴, in the presence of abase; or

(C) the reaction of a compound of the formula (10)

with a compound of the formula (13):

under nucleophilic substitution conditions; wherein R¹, R², R³, R⁴, X¹,X², W, Y, Z, m, p and q are as defined in any one of Embodiments 1.1 to1.84; and optionally:

(D) converting one compound of the formula (1) or formula (1a) toanother compound of the formula (1) or formula (1a).

In process variant (A), the piperidine heterocycle (10) is reacted withthe substituted ketone (11) under reductive amination conditions. Thereductive amination reaction is typically carried out at ambienttemperature using a borohydride reducing agent such as sodiumtriacetoxy-borohydride in a solvent such as dichloromethane ordichloroethane containing acetic acid.

In process variant (C), the piperidine heterocycle (10) is reacted withthe sulfonic ester (13, R=methyl or 4-methylbenzyl) in a nucleophilicsubstitution reaction which is typically carried out with mild heating(e.g. to a temperature of from about 40° C. to about 70° C.) eitherneat, with no solvent, or in a suitable solvent such as tetrahydrofuran,acetonitrile or dimethylacetamide

Intermediate compounds of the formula (12) can be prepared by the seriesof reactions shown in Scheme 1 below.

In reaction Scheme 1, the piperidine heterocycle (10) is reacted withthe Boc-protected ketone (14) under reductive amination conditions. Thereductive amination reaction is typically carried out with mild heating(e.g. to a temperature of from about 40° C. to about 70° C.) in thepresence of either sodium cyanoborohydride in combination with zincchloride or sodium triacetoxyborohydride in combination with titaniumisopropoxide in a solvent such as dichloromethane or dichloroethanecontaining acetic acid to give an intermediate piperidine compound (15)which is then deprotected by removal of the Boc group by treatment withacid (e.g. trifluoroacetic acid in dichloromethane) to give the compound(12).

Compounds of the formula (12) can also be prepared by the sequence ofreactions shown in Scheme 2 below.

In Scheme 2, the Boc-protected ketone (14) is reduced to the alcohol(16) using sodium borohydride in methanol. The alcohol (16) is thenactivated as the sulfonic ester (17, R=methyl or 4-methylbenzyl) usingthe corresponding sulfonyl chloride in dichloromethane in the presenceof a tertiary amine such as triethylamine or N,N-diisopropylethylamine.The sulfonic ester (17) is reacted with the piperidine heterocycle (10)in a nucleophilic substitution reaction which is typically carried outwith mild heating (e.g. to a temperature of from about 40° C. to about70° C.) either neat, with no solvent, or in a suitable solvent such astetrahydrofuran, acetonitrile or dimethylacetamide to give compound(15), which is then deprotected by removal of the Boc group by treatmentwith acid (e.g. trifluoroacetic acid in dichloromethane) to give thecompound (12).

Once formed, one compound of the formula (1) or formula (1a), or aprotected derivative thereof, can be converted into another compound ofthe formula (1) or formula (1a) by methods well known to the skilledperson. Examples of synthetic procedures for converting one functionalgroup into another functional group are set out in standard texts suchas Advanced Organic Chemistry and Organic Syntheses (see referencesabove) or Fiesers' Reagents for Organic Synthesis, Volumes 1-17, JohnWiley, edited by Mary Fieser (ISBN: 0-471-58283-2).

In many of the reactions described above, it may be necessary to protectone or more groups to prevent reaction from taking place at anundesirable location on the molecule. Examples of protecting groups, andmethods of protecting and deprotecting functional groups, can be foundin Protective Groups in Organic Synthesis (T. Greene and P. Wuts; 3rdEdition; John Wiley and Sons, 1999).

Compounds made by the foregoing methods may be isolated and purified byany of a variety of methods well known to those skilled in the art andexamples of such methods include recrystallisation and chromatographictechniques such as column chromatography (e.g. flash chromatography) andHPLC.

Pharmaceutical Formulations

While it is possible for the active compound to be administered alone,it is preferable to present it as a pharmaceutical composition (e.g.formulation).

Accordingly, in another embodiment (Embodiment 4.1) of the invention,there is provided a pharmaceutical composition comprising at least onecompound of the formula (1) or formula (1a) as defined in any one ofEmbodiments 1.1 to 1.84 together with at least one pharmaceuticallyacceptable excipient.

In one embodiment (Embodiment 4.2), the composition is a tabletcomposition.

In another embodiment (Embodiment 4.3), the composition is a capsulecomposition.

The pharmaceutically acceptable excipient(s) can be selected from, forexample, carriers (e.g. a solid, liquid or semi-solid carrier),adjuvants, diluents (e.g solid diluents such as fillers or bulkingagents; and liquid diluents such as solvents and co-solvents),granulating agents, binders, flow aids, coating agents,release-controlling agents (e.g. release retarding or delaying polymersor waxes), binding agents, disintegrants, buffering agents, lubricants,preservatives, anti-fungal and antibacterial agents, antioxidants,buffering agents, tonicity-adjusting agents, thickening agents,flavouring agents, sweeteners, pigments, plasticizers, taste maskingagents, stabilisers or any other excipients conventionally used inpharmaceutical compositions.

The term “pharmaceutically acceptable” as used herein means compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof a subject (e.g. a human subject) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each excipient mustalso be “acceptable” in the sense of being compatible with the otheringredients of the formulation.

Pharmaceutical compositions containing compounds of the formula (1) orformula (1a) can be formulated in accordance with known techniques, seefor example, Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., USA.

The pharmaceutical compositions can be in any form suitable for oral,parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic,otic, rectal, intra-vaginal, or transdermal administration.

Pharmaceutical dosage forms suitable for oral administration includetablets (coated or uncoated), capsules (hard or soft shell), caplets,pills, lozenges, syrups, solutions, powders, granules, elixirs andsuspensions, sublingual tablets, wafers or patches such as buccalpatches.

Tablet compositions can contain a unit dosage of active compoundtogether with an inert diluent or carrier such as a sugar or sugaralcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugarderived diluent such as sodium carbonate, calcium phosphate, calciumcarbonate, or a cellulose or derivative thereof such as microcrystallinecellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, and starches such as corn starch. Tablets may also containsuch standard ingredients as binding and granulating agents such aspolyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymerssuch as crosslinked carboxymethylcellulose), lubricating agents (e.g.stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT),buffering agents (for example phosphate or citrate buffers), andeffervescent agents such as citrate/bicarbonate mixtures. Suchexcipients are well known and do not need to be discussed in detailhere.

Tablets may be designed to release the drug either upon contact withstomach fluids (immediate release tablets) or to release in a controlledmanner (controlled release tablets) over a prolonged period of time orwith a specific region of the GI tract.

The pharmaceutical compositions typically comprise from approximately 1%(w/w) to approximately 95%, preferably % (w/w) active ingredient andfrom 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient(for example as defined above) or combination of such excipients.Preferably, the compositions comprise from approximately 20% (w/w) toapproximately 90% (w/w) active ingredient and from 80% (w/w) to 10% of apharmaceutically excipient or combination of excipients. Thepharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, pre-filled syringes, dragées, powders,tablets or capsules.

Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5%lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/or bulking agents(depending on drug dose). They may also contain 0-10% (w/w) polymerbinders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments. Slow releasetablets would in addition typically contain 0-99% (w/w)release-controlling (e.g. delaying) polymers (depending on dose). Thefilm coats of the tablet or capsule typically contain 0-10% (w/w)polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers.

Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50%(w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI)(depending on dose and if freeze dried). Formulations for intramusculardepots may also contain 0-99% (w/w) oils.

The pharmaceutical formulations may be presented to a patient in“patient packs” containing an entire course of treatment in a singlepackage, usually a blister pack.

The compounds of the formula (1) or formula (1a) will generally bepresented in unit dosage form and, as such, will typically containsufficient compound to provide a desired level of biological activity.For example, a formulation may contain from 1 nanogram to 2 grams ofactive ingredient, e.g. from 1 nanogram to 2 milligrams of activeingredient. Within these ranges, particular sub-ranges of compound are0.1 milligrams to 2 grams of active ingredient (more usually from 10milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1microgram to 20 milligrams (for example 1 microgram to 10 milligrams,e.g. 0.1 milligrams to 2 milligrams of active ingredient).

For oral compositions, a unit dosage form may contain from 1 milligramto 2 grams, more typically 10 milligrams to 1 gram, for example 50milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.

The active compound will be administered to a patient in need thereof(for example a human or animal patient) in an amount sufficient toachieve the desired therapeutic effect (effective amount). The preciseamounts of compound administered may be determined by a supervisingphysician in accordance with standard procedures.

EXAMPLES

The invention will now be illustrated, but not limited, by reference tothe specific embodiments described in the following examples.

Examples 1-1 to 9-2

The compounds of Examples 1-1 to 9-2 shown in Table 1 below have beenprepared. Their NMR and LCMS properties and the methods used to preparethem are set out in Table 3. The starting materials for each of theExamples are listed in Table 2.

TABLE 1

Example 1-1

Example 2-1

Example 2-2

Example 2-3

Example 2-4

Example 2-5

Example 2-6

Example 2-7

Example 2-8

Example 2-9

Example 2-10

Example 2-11

Example 2-12

Example 2-13

Example 2-14

Example 2-15

Example 2-15

Example 2-16

Example 2-17

Example 2-18

Example 2-19

Example 2-20

Example 2-21

Example 2-22

Example 2-23

Example 2-24

Example 2-25

Example 2-26

Example 2-27

Example 2-28

Example 2-29

Example 2-30

Example 2-31

Example 2-32

Example 2-33

Example 2-34

Example 2-35

Example 3-1

Example 3-2

Example 3-3

Example 3-4

Example 3-5

Example 4-1

Example 5-1

Example 5-2

Example 5-3

Example 5-4

Example 6-1

Example 6-2

Example 6-3

Example 7-1

Example 8-1

Example 9-1

Example 9-2

Example 9-2

General Procedures

Where no preparative routes are included, the relevant intermediate iscommercially available. Commercial reagents were utilized withoutfurther purification. Room temperature (rt) refers to approximately20-27° C. ¹H NMR spectra were recorded at 300 or 400 MHz on either aBruker or Varian instrument. Chemical shift values are expressed inparts per million (ppm), i.e. (δ)-values. The following abbreviationsare used for the multiplicity of the NMR signals: s=singlet, br=broad,d=doublet, t=triplet, q=quartet, quint=quintet, td=triplet of doublets,tt=triplet of triplets, qd=quartet of doublets, ddd=doublet of doubletof doublets, ddt=doublet of doublet of triplets, m=multiplet. Couplingconstants are listed as J values, measured in Hz. NMR and massspectroscopy results were corrected to account for background peaks.Chromatography refers to column chromatography performed using 60-120mesh silica gel and executed under nitrogen pressure (flashchromatography) conditions. TLC for monitoring reactions refers to TLCrun using the specified mobile phase and Silica gel F254 (Merck) as astationary phase. Microwave-mediated reactions were performed in BiotageInitiator or CEM Discover microwave reactors.

LCMS experiments were typically carried out using electrosprayconditions as specified for each compound under the followingconditions:

LCMS Methods A and B

Instruments: Waters Alliance 2795, Waters 2996 PDA detector, MicromassZQ; Column: Waters X-Bridge C-18, 2.5 micron, 2.1×20 mm or PhenomenexGemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time (min)/solvent Din C(%)]: Method A: 0.00/2, 0.10/2, 2.50/95, 3.50/95, 3.55/2, 4.00/2 orMethod B: 0.00/2, 0.10/2, 8.40/95, 9.40/95, 9.50/2, 10.00/2; Solvents:solvent C=2.5 L H₂O+2.5 mL ammonia solution; solvent D=2.5 L MeCN+135 mLH₂O+2.5 mL ammonia solution); Injection volume 3 μL; UV detection 230 to400 nM; column temperature 45° C.; Flow rate 1.5 mL/min.

LCMS Method C

Instruments: Agilent 1260 Infinity LC with Diode Array Detector, Agilent6120B Single Quadrupole MS with API-ES Source; Column: PhenomenexGemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time (min)/solvent B in A(%)]: Method: 0.00/5, 2.00/95, 2.50/95, 2.60/5, 3.00/5; Solvents:solvent A=2.5 L H₂O+2.5 mL of (28% NH3 in H₂O); solvent B=2.5 L MeCN+129mL H₂O+2.7 mL of (28% NH3 in H₂O); Injection volume 0.5 μL; UV detection190 to 400 nM; column temperature 40° C.; Flow rate 1.5 m L/m in.

LCMS Methods D and E

Instruments: HP 1100 with G1315A DAD, Micromass ZQ; Column: WatersX-Bridge C-18, 2.5 micron, 2.1×20 mm or Phenomenex Gemini-NX C-18, 3micron, 2.0×30 mm; Gradient [time (min)/solvent D in C (%)]: Method D:0.00/2, 0.10/2, 2.50/95, 3.50/95, 3.55/2, 4.00/2 or Method E: 0.00/2,0.10/2, 8.40/95, 9.40/95, 9.50/2, 10.00/2; Solvents: solvent C=2.5 LH₂O+2.5 mL 28% ammonia in H₂O solution; solvent D=2.5 L MeCN+135 mLH₂O+2.5 mL 28% ammonia in H₂O solution); Injection volume 1 μL; UVdetection 230 to 400 nM; Mass detection 130 to 800 AMU (+ve and −veelectrospray); column temperature 45° C.; Flow rate 1.5 mL/min.

LCMS Method F:

Instruments: Waters Acquity H Class, Photo Diode Array, SQ Detector;Column: BEH C18, 1.7 micron, 2.1×50 mm; Gradient [time (min)/solvent Bin A (%)]: 0.00/5, 0.40/5, 0.8/35, 1.20/55, 2.50/100, 3.30/100 4.00/5;Solvents: solvent A=5 mM ammonium acetate and 0.1% formic acid in H₂O;solvent B=0.1% formic acid in MeCN; Injection volume 2 μL; UV detection200 to 400 nM; Mass detection 100 to 1200 AMU (+ve electrospray); columnat ambient temperature; Flow rate 0.5 mL/min.

LCMS Method G:

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column:X-Bridge C18, 5 micron, 150×4.6 mm; Gradient [time (min)/solvent B in A(%)]: 0.00/10, 5.00/90, 7.00/100, 11.00/100, 11.01/10 12.00/10;Solvents: solvent A=0.1% ammonia in H₂O; solvent B=0.1% ammonia in MeCN;Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to1000 AMU (+ve electrospray); column at ambient temperature; Flow rate1.0 mL/min.

LCMS Method H:

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column:X-Bridge C18, 5 micron, 150×4.6 mm; Gradient [time (min)/solvent B in A(%)]: 0.00/100, 7.00/50, 9.00/0, 11.00/0, 11.01/100, 12.00/100;Solvents: solvent A=0.1% ammonia in H₂O; solvent B=0.1% ammonia in MeCN;Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to1000 AMU (+ve electrospray); column at ambient temperature; Flow rate1.0 mL/min.

LCMS Method I:

Instruments: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column:Acquity HSS-T3, 1.8 micron, 2.1×100 mm; Gradient [time (min)/solvent Bin A (%)]: 0.00/10, 1.00/10, 2.00/15, 4.50/55, 6.00/90, 8.00/90,9.00/10, 10.00/10; Solvents: solvent A=0.1% trifluoroacetic acid inwater; solvent B=acetonitrile; Injection volume 14; Detection wavelength214 nm; Column temperature 30° C.; Flow rate 0.3 mL per min.

LCMS Method J:

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column:X-Bridge C18, 3.5 micron, 50×4.6 mm; Gradient [time (min)/solvent B in A(%)]: 0.01/0, 0.20/0, 5.00/90, 5.80/95, 7.20/95, 7.21/100, 10.00/100;Solvents: solvent A=0.1% ammonia in H₂O; solvent B=0.1% ammonia in MeCN;Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to1000 AMU (+ve electrospray); column at ambient temperature; Flow rate1.0 mL/min.

LCMS data in the experimental section are given in the format: Mass ion,retention time, UV activity.

Abbreviations

d=day(s)

DCE=dichloroethane

DCM=dichloromethane

DIPEA=diisopropylethylamine

DMF=dimethylformamide

DMSO=dimethylsulfoxide

DPPA=diphenylphosphorylazide

ES=electro spray ionisation

Et₃N=triethylamine

EtOAc=ethyl acetate

h=hour(s)

HPLC=high performance liquid chromatography

LC=liquid chromatography

LDA=Lithium diisopropylamide

LiHMDS=Lithium bis(trimethylsilyl)amide

MeCN=acetonitrile

MeOH=methanol

min=minute(s)

MS=mass spectrometry

N₂=nitrogen

NaCNBH₃=sodium cyanoborohydride

NMR=nuclear magnetic resonance

rt=room temperature

sat.=saturated

sol.=solution

SFC=supercritical fluid chromatography

STAB=sodium triacetoxyborohydride

TBAF=tetra butyl ammonium fluoride

THF=tetrahydrofuran

TLC=thin layer chromatography

Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal,secondary, iso, and tertiary.

Synthesis of Intermediates: Route 1 Typical Procedure for thePreparation of Piperidines, as Exemplified by the Preparation ofIntermediate 3, 1-ethyl-2,8-diazaspiro[4.5]decan-3-one.HCl

Sodium hydride in mineral oil (60%, 11.9 g, 297 mmol) was dissolved inDMF (200 mL) and methyl 2-(dimethoxyphosphoryl)acetate (52.0 g, 286mmol) was added drop wise at 0° C. The reaction mixture was stirred at0° C. for 20 min then tert-butyl 4-oxopiperidine-1-carboxylate (45.5 g,228 mmol) in DMF (100 mL) was added drop wise at 0° C. The reactionmixture was stirred at rt for 2 h, then diluted with ice water (20 mL),filtered and the solvents were removed in vacuo to give tert-butyl4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (42.5 g, 72.9%) asa yellow solid.

LCMS (Method F): m/z 256 (M+H)⁺ (ES⁺), at 2.47 min, UV active

tert-Butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (5.0 g,19.60 mmol) was dissolved in THF (50.0 mL) then 1.0M TBAF in THF (25.5mL, 25.5 mmol) was added drop wise to reaction mixture followed by1-nitro propane (2.62 g, 29.4 mmol), the reaction mixture was heated to70° C. for 24 h. Reaction mixture was poured onto ice cold water (150mL), extracted by EtOAc (500 mL), aqueous layer was further extractedwith EtOAc (2×250 mL), organic layers were combined, dried (Na₂SO₄).Solvents were removed in vacuo and the residue was purified by columnchromatography (normal phase silica, 0 to 6% EtOAc in Hexane) to givetert-butyl 4-(2-methoxy-2-oxoethyl)-4-(1-nitropropyl)piperidine-1-carboxylate (1.1 g, 40.9%) as yellow oil.

LCMS (Method F): m/z 345 (M+H)⁺ (ES⁺), at 2.43 min, UV inactive

tert-Butyl4-(2-methoxy-2-oxoethyl)-4-(1-nitropropyl)piperidine-1-carboxylate (0.7g, 2.03 mmol) was dissolved in MeOH (15 mL) and Raney®-Nickel (140.0 mg,20% w/w) was added. The reaction mixture was purged with H₂ gas and thenstirred at rt for 16 h. The reaction mixture was filtered through celiteand solvents were removed in vacuo to give tert-butyl1-ethyl-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.28 g, 48.0%) aswhite solid.

LCMS (Method F): m/z 283 (M+H)⁺ (ES⁺), at 1.95 min, UV inactive

tert-Butyl 1-ethyl-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.27g, 0.96 mmol) was dissolved 4.0 M HCl in 1,4-dioxane (5.0 mL) at roomtemperature. The reaction mixture was stirred at rt for 16 h and thensolvents were removed in vacuo. Residue was triturated with diethylether to give 1-ethyl-2,8-diazaspiro[4.5]decan-3-one.HCl,

Intermediate 3 (0.15 g, 84.7%) as white solid.

The data for the title compound are in Table 2

Route 2 Typical Procedure for the Preparation of Ketones, as Exemplifiedby the Preparation of Intermediate 6,6-fluoro-2,8-diazaspiro[4.5]decan-3-one.HCl

Sodium hydride in mineral oil (60%, 0.18 g, 4.6 mmol) was suspended inTHF (12 mL) and methyl 2-(dimethoxyphosphoryl)acetate (0.84 g, 4.6 mmol)was added drop wise at 0° C. The reaction mixture was stirred at 0° C.for 1 h then tert-butyl-3-fluoro-4-oxo-piperidine-1-carboxylate (1.0 g,4.6 mmol) in THF (5 mL) was added drop wise at 0° C. The reactionmixture was stirred at rt for 16 h, then quenched with water (10 mL).The reaction mixture was extracted with EtOAc (3×20 mL), the organiclayers were combined and washed with sat. NaHCO₃ sol. (20 mL) and brine(20 mL) then dried (Na₂SO₄). The solvents were removed in vacuo and theresidue was purified by column chromatography (normal phase, [BiotageSNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25 mL per min, gradient 0%to 35% EtOAc in Isohexane]) to give tert-butyl3-fluoro-4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (0.94 g,75%).

¹H NMR: (400 MHz, DMSO-d₆) δ: 1.39 (d, J=2.5 Hz, 9H), 2.20-2.35 (m, 1H),2.74-2.96 (m, 2H), 3.64 (d, J=2.0 Hz, 3H), 4.02-4.20 (m, 1H), 4.22-4.43(m, 1H), 5.05 (ddd, J=47.5, 4.5, 3.5 Hz, 1H), 5.98 (s, 1H), 6.19 (s,0.5H), 6.31 (s, 0.5H)

tert-Butyl3-fluoro-4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (0.94 g,3.5 mmol) and nitromethane (0.32 g, 5.2 mmol) were dissolved in 1.0 MTBAF in THF (10 mL), the reaction mixture was heated at 50° C. under N₂for 2 d. The solvents were removed in vacuo and the residue was purifiedby column chromatography (normal phase, [Biotage SNAP cartridge KP-sil25 g, 40-63 μm, 60 Å, 25 mL per min, gradient 0% to 40% EtOAc inIsohexane]) to give tert-butyl3-fluoro-4-(2-methoxy-2-oxoethyl)-4-(nitromethyl)piperidine-1-carboxylate(0.47 g, 41%).

¹H NMR: (400 MHz, DMSO-d₆) δ: 1.37 (s, 9H), 1.59-1.74 (m, 2H), 2.62-2.71(m, 1H), 2.71-2.83 (m, 1H), 2.94-3.08 (m, 1H), 3.16-3.28 (m, 1H), 3.60(s, 3H), 3.66-3.84 (m, 1H), 3.94-4.07 (m, 1H), 4.64-4.71 (m, 1H),4.71-4.86 (m, 2H)

tert-Butyl3-fluoro-4-(2-methoxy-2-oxoethyl)-4-(nitromethyl)piperidine-1-carboxylate(0.47 g, 1.41 mmol) was dissolved in EtOH (50 mL) and passed three timesthrough an H-Cube® fitted with a ThalesNano CatCart® catalyst cartridgesystem, 70 mm Raney®-Nickel (THS01132) at 40 Bar and 50° C. The solventswere removed in vacuo to give tert-butyl6-fluoro-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.35 g, 85%) asa white solid which was used without further purification.

¹H NMR: (400 MHz, DMSO-d₆) δ: 1.37 (s, 9H), 1.42-1.56 (m, 1H), 1.56-1.74(m, 1H), 2.12 (s, 2H), 2.84-2.92 (m, 1H), 2.94-3.06 (m, 1H), 3.06-3.21(m, 1H), 3.28 (d, J=9.5 Hz, 1H), 3.71-3.83 (m, 1H), 3.83-4.02 (m, 1H),4.41-4.60 (m, 1H), 7.58-7.70 (m, 1H)

tert-butyl 6-fluoro-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.35g, 1.27 mmol) was suspended in 4 M HCl in 1,4-dioxane (10 mL) andstirred at rt for 16 h. The solvents were removed in vacuo to give6-fluoro-2,8-diazaspiro[4.5]decan-3-one.HCl, Intermediate 6 (0.27 g,assume 100%) as a white solid which was used without furtherpurification.

The data for the title compound are in Table 2

Route 3 For the Preparation of Intermediate 7,2-ethyl-2,8-diazaspiro[4.5]decan-3-one.HCl

Sodium hydride in mineral oil (60%, 11.9 g, 297 mmol) was dissolved inDMF (200 mL) and methyl 2-(dimethoxyphosphoryl)acetate (52.0 g, 286mmol) was added drop wise at 0° C. The reaction mixture was stirred at0° C. for 20 min then tert-butyl 4-oxopiperidine-1-carboxylate (45.5 g,228 mmol) in DMF (100 mL) was added drop wise at 0° C. The reactionmixture was stirred at rt for 2 h, then diluted with ice water (20 mL),filtered and the solvents were removed in vacuo to give tert-butyl4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (42.5 g, 72.9%) asa yellow solid.

LCMS (Method F): m/z 256 (M+H)⁺ (ES⁺), at 2.47 min, UV active

tert-Butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (42.5g, 166 mmol) and nitro methane (11.2 g, 183 mmol) were dissolved in THF(200 mL), 1.0 M solution of TBAF in THF (250 mL, 250 mmol) was addeddrop wise at 0° C. The reaction mixture was refluxed at 70° C. for 16 h.The reaction mixture was partitioned between H₂O (150 mL) and EtOAc (90mL), the aqueous layer was further extracted with EtOAc (2×90 mL); theorganic layers were combined and dried (Na₂SO₄). The solvent was removedin vacuo and the residue was purified by column chromatography(normal-phase silica, 0 to 30% EtOAc in Hexanes) to give tert-butyl4-(2-methoxy-2-oxoethyl)-4-(nitromethyl)piperidine-1-carboxylate (40.3g, 76.5%) as a white solid.

LCMS (Method F): m/z 261 (M+H-56)⁺ (ES⁺), at 2.30 min, UV inactive

tert-Butyl 4-(2-methoxy-2-oxoethyl)-4-(nitromethyl)piperidine-1-carboxylate (40.0 g, 126 mmol) and Raney-Nickel (40.0 g)were dissolved in EtOH (800 mL) and the reaction mixture was purged withH₂ gas for 16 hrs. The reaction mixture was filtered through celite,washed with MeOH and the solvent was removed in vacuo. The residue waspurified by column chromatography (normal-phase silica, 0 to 4% MeOH inDCM) to give tert-butyl 3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate(22.9 g, 71.2%) as a white solid.

LCMS (Method F): m/z 255 (M+H)⁺ (ES⁺), at 1.81 min, UV inactive

60% NaH (0.63 g, 15.7 mmol) was dissolved in DMF (15.0 mL) andtert-butyl 3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (1.00 g, 3.92mmol) in DMF (5 mL) was added drop wise at 0° C. The reaction mixturewas stirred at 0° C. for 30 min, then ethyl iodide (0.48 mL, 5.88 mmol)was added drop wise and the reaction mixture was allowed to warm to rtand stirred for 1 h. The reaction mixture was partitioned between H₂O(30 mL) and EtOAc (25 mL), the aqueous layer was further extracted withEtOAc (2×25 mL), the organic layers were combined and dried (Na₂SO₄).The solvent was removed in vacuo and the residue was purified by columnchromatography (normal-phase silica, 0 to 3% MeOH in DCM) to givetert-butyl 2-ethyl-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (1.0 g,90.3%) as a white solid.

LCMS (Method F): m/z 283 (M+H)⁺ (ES⁺), at 2.00 min, UV inactive

tert-Butyl 2-ethyl-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (1.00g, 3.54 mmol) was dissolved in 4.0 M HCl in 1,4-dioxane (15.0 mL) andreaction mixture was stirred at rt for 5 h. The solvent was removed invacuo and the residue was triturated with acetone (3×10 mL) to give2-ethyl-2,8-diazaspiro[4.5]decan-3-one.HCl, Intermediate 7 (0.55 g,71.2%) as a white solid.

The data for the title compound are in Table 2

Route 4 Typical Procedure for the Preparation of Piperidines, asExemplified by the Preparation of Intermediate 12,4,4-dimethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one

2-Bromo-2-methylpropionic acid ethyl ester (15.4 g, 79.2 mmol) wasdissolved in Et₂O (100 mL) and cooled to −78° C. under N₂. n-Butyllithium (99 mL, 158 mmol) was added drop wise and the reaction mixturewas stirred at −78° C. for 1 h. N-benzyl-4-piperidone (10 g, 52.8 mmol)in Et₂O (100 mL) was added drop wise and the reaction mixture wasstirred at −60° C. for 2 h. The reaction mixture was quenched with sat.NH₄Cl sol. (200 mL) and then diluted with water (500 mL). The reactionmixture was extracted with EtOAc (3×200 mL), the organic layers werecombined and dried (Na₂SO₄). The solvent was removed in vacuo and theresidue was purified by column chromatography (normal phase, neutralsilica gel, 60-120 mesh, 0 to 15% EtOAc in Hexane) to give ethyl2-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methylpropanoate (12.0 g, 74.3%)as a yellow gum

LCMS (Method F): m/z 306 (M+H)⁺ (ES⁺), at 1.79 min, UV active

Ethyl 2-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methylpropanoate (12.0 g,39.3 mmol) and 85% hydrazine hydrate (80 mL) were dissolved in EtOH (30mL). The reaction mixture was refluxed at 100° C. for 120 h. The solventwas removed in vacuo to give2-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methylpropanohydrazide (15.0 g,131%) as a yellow gum, which was used crude in the next step.

LCMS (Method F): m/z 292 (M+H)⁺ (ES⁺), at 1.37 min, UV active

2-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methylpropanohydrazide (15 g,assumed 39.3 mmol) was dissolved in water (60 mL) and then acidifiedwith conc HCl (5 mL), the reaction mixture was cooled to 5° C. NaNO₂(4.2 g, 61.8 mmol) in water (8 mL) was added at 0° C. and the reactionmixture was warmed to 60° C. for 1 h. The reaction mixture was basifiedwith 20% NaOH solution and diluted with water (500 mL), extracted withEtOAc (3×200 mL), the organic layers were combined and dried (Na₂SO₄).The solvent was removed in vacuo and the residue was purified by columnchromatography (normal phase, neutral silica gel, 60-120 mesh, 0 to 2%MeOH in DCM) to give 8-benzyl-4, 4-dimethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one (5.0 g, 46.4%[over two steps]) as a yellow solid.

LCMS (Method F): m/z 275 (M+H)⁺ (ES⁺), at 1.50 min, UV active

8-Benzyl-4,4-dimethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one (5.0 g, 18.2mmol) was dissolved in MeOH (30 mL). 10% Pd/C (0.5 g) was added and thereaction mixture was stirred under H₂ atmosphere (1 atm) at 50° C. for 2h. The reaction mixture was filtered through celite and the solvents wasremoved in vacuo. The residue was triturated with Et₂O to give4,4-dimethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, Intermediate 12 (1.5g, 45.4%) as a yellow solid.

The data for the title compound are in Table 2

Route 5 Typical Procedure for the Preparation of Ketones, as Exemplifiedby the Preparation of Intermediate 16, methyl3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate

Nortropinone. HCl (1.00 g, 6.1 mmol) was suspended in DCM (20 mL) andcooled to 0° C. under N₂, triethylamine (1.25 g, 12.4 mmol) and methylchloroformate (0.64 g, 6.8 mmol) were added and the reaction mixture wasstirred at rt for 16 h. The reaction mixture was diluted with DCM (20mL) and washed with sat. NaHCO₃ sol. (20 mL) and brine (20 mL) thendried (MgSO₄), the solvents were removed in vacuo. The residue waspurified by column chromatography (normal phase, [Biotage SNAP cartridgeKP-sil 25 g, 40-63 μm, 60 Å, 25 mL per min, gradient 0% to 6% MeOH inDCM]) to give methyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate,Intermediate 16 (0.88 g, 77.6%) as a pale yellow gum.

The data for the title compound are in Table 2

Route 6 Typical Procedure for the Preparation of Ketones, as Exemplifiedby the Preparation of Intermediate 34, ethyl3-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate

tert-Butyl 3-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate (0.60 g, 2.7mmol) was added portionwise to 4.0 M HCl in 1,4-Dioxane (10 mL, 40mmol), the reaction mixture was stirred at rt for 24 h and then thesolvents were removed in vacuo. The residue was dissolved in DCM (10 mL)and Et₃N (0.75 mL, 5.4 mmol) and cooled to 0° C. Ethyl chloroformate(0.28 mL, 3.0 mmol) was added drop wise and the reaction mixture wasstirred at rt for 18 h. The reaction mixture was partitioned between DCM(10 mL) and sat. NaHCO₃ sol. (10 mL), the aqueous layer was extractedwith DCM (2×10 mL). The organic layers were combined and washed withbrine (10 mL), dried over (MgSO₄), and the solvents were removed invacuo to give ethyl 3-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate,Intermediate 34 (0.43 g, 81%) as an yellow gum.

The data for the title compound are in Table 2

Route 7 Typical Procedure for the Preparation of Activated Carbamates,as Exemplified by the Preparation of Intermediate 58, 4-nitrophenyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

2,8-Diazaspiro[4.5]decan-3-one (1.12 g, 7.24 mmol) and 4-nitrophenyl3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (2.10 g, 7.24 mmol) weredissolved in DCM (10 mL), treated with titanium (IV) isopropoxide (2.57g, 9.05 mmol), then stirred at rt under nitrogen overnight. The reactionmixture was diluted with MeOH (30 mL) and NaCNBH₃ (0.91 g, 14.48 mmol)was added and the reaction mixture was stirred at rt under nitrogenovernight. Water (10 mL) and DCM (10 mL) were added and the solution waspassed through a celite pad to remove solids. The filtrate was separatedand the aqueous phase was extracted with DCM (3×25 mL). The organicphases were combined and washed with sat. NaHCO₃ sol. (25 ml) and driedby passing down a Biotage Phase Separator cartridge. The solvents wereremoved in vacuo, and the residue was purified by column chromatography(normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 Å, 10mL per min, gradient 0% to 10% MeOH in DCM]) to give 4-nitrophenyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,Intermediate 58 as a mixture of diastereoisomers, (204 mg, 6.6%) as ayellow glassy solid.

The data for the title compound are in Table 2

Route 8 Typical Procedure for the Preparation of Piperidines, asExemplified by the Preparation of Intermediate 67,1-benzyl-1,2,8-triazaspiro[4.5]decan-3-one HCl

Sodium hydride in mineral oil (60%, 11.9 g, 297 mmol) was dissolved inDMF (200 mL) and methyl 2-(dimethoxyphosphoryl)acetate (52.0 g, 286mmol) was added drop wise at 0° C. The reaction mixture was stirred at0° C. for 20 min then tert-butyl 4-oxopiperidine-1-carboxylate (45.5 g,228 mmol) in DMF (100 mL) was added drop wise at 0° C. The reactionmixture was stirred at rt for 2 h, then diluted with ice water (20 mL),filtered and the solvents were removed in vacuo to give tert-butyl4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (42.5 g, 72.9%) asa yellow solid.

LCMS (Method F): m/z 256 (M+H)⁺ (ES⁺), at 2.47 min, UV active

To tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (3.0g, 11.8 mmol) in EtOH (20 mL) was added hydrazine hydrate (1.1 mL, 23.5mmol) and the reaction mixture was stirred at 80° C. for 8 h. Themixture was partitioned between water (150 mL) and EtOAc (120 mL), theaqueous layer was further extracted with EtOAc (2×120 mL), and combinedorganics were washed with brine (100 mL) and dried (Na₂SO₄). Thesolvents were removed in vacuo and the residue was purified by columnchromatography (normal silica, mesh size: 60-120, 4.0% to 10.0% MeOH inDCM) to give tert-butyl 3-oxo-1, 2,8-triazaspiro[4.5]decane-8-carboxylate (1.78 g, 59.3%) as white solid.

LCMS (Method F): m/z 256 (M+H)⁺ (ES⁺), at 1.70 min, UV inactive

tert-Butyl 3-oxo-1,2,8-triazaspiro[4.5]decane-8-carboxylate (0.3 g, 1.18mmol), benzaldehyde (0.12 mL, 1.29 mmol), ZnCl₂ (8.0 mg, 0.06 mmol) andEt₃N (0.80 mL, 5.89 mmol) were dissolved in MeOH (10 mL) and thereaction mixture stirred at 50° C. for 2 h. The mixture was then cooledto 0° C. before addition of NaCNBH₃ (222 mg, 3.52 mmol) portionwise andfurther stirring at 40° C. for 30 h. The mixture was partitioned betweenH₂O (60 mL) and EtOAc (40 mL), and the aqueous layer further extractedwith EtOAc (2×40 mL). Combined organics were dried (Na₂SO₄), the solventwas removed in vacuo and the crude residue purified by trituration withhexane (3×3 mL) to give tert-butyl 1-benzyl-3-oxo-1,2,8-triazaspiro[4.5] decane-8-carboxylate (320 mg, 79.0%) as a yellow gum.

LCMS (Method G): m/z 346 (M+H)⁺ (ES⁺), at 5.91 min, UV active

tert-Butyl 1-benzyl-3-oxo-1,2,8-triazaspiro[4.5]decane-8-carboxylate(0.3 g, 0.87 mmol) was dissolved in 1,4-dioxane (2 mL) and 4.0 M HCl in1,4-dioxane (10 mL) was added drop wise, the reaction mixture wasstirred at 30° C. for 16 h. The solvents were removed in vacuo and theresidue was purified by triturating with Et₂O (3×3 mL) to give1-benzyl-1,2,8-triazaspiro[4.5]decan-3-one, Intermediate 67 (0.21 g,98.6%) as an off-white solid.

The data for the title compound are in Table 2

Route 9 Typical Procedure for the Preparation of Ketones as Exemplifiedby the Preparation of Intermediate 77, S-ethyl3-oxo-8-azabicyclo[3.2.1]octane-8-carbothioate

To tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 4.4mmol) in 1,4-dioxane (3 mL) was added 4.0 M HCl in 1,4-dioxane (10 mL,40 mmol), the reaction mixture was stirred at 30° C. for 7 h and thenthe solvents were removed in vacuo. To a portion of the residue (0.20 g,1.3 mmol) in DCM (10 mL) was added DIPEA (0.40 mL, 2.5 mmol),ethanethiol (0.10 mL, 1.8 mmol) and 1,1-carbonyldiimidazole (0.29 g, 1.8mmol) and the mixture stirred at rt for 18 h. The reaction mixture waspartitioned between H₂O (100 mL) and EtOAc (70 mL) and the aqueous layerfurther extracted with EtOAc (2×70 mL). Combined organics were driedover Na₂SO₄ and the solvent was removed in vacuo. The residue waspurified by column chromatography (Normal silica, mesh size: 60-120, 20%to 30% EtOAc in Hexane) to give S-ethyl3-oxo-8-azabicyclo[3.2.1]octane-8-carbothioate, Intermediate 77 (120 mg,45.1%) as a yellow oil.

The data for the title compound are in Table 2

Route 10 Typical Procedure for the Preparation of Intermediate 80,1-oxa-3,8-diazaspiro[4.6]undecan-2-one

Azepan-4-one HCl (32 g, 214 mmol), benzyl bromide (40 g, 235 mmol),K₂CO₃ (36 g, 257 mmol) and water (40 mL) were dissolved in THF (160 mL)and stirred at 50° C. for 3 h. The reaction mixture was diluted with H₂O(500 mL), extracted with EtOAc (3×200 mL), and combined organics dried(Na₂SO₄) and the solvents were removed in vacuo. The crude residue waspurified by column chromatography (Normal phase, Neutral silica gel,60-120 mesh, 0 to 15% EtOAc in hexane) to give 1-benzoylazepan-4-one(18.0 g, 41.5%) as a yellow liquid.

LCMS (Method F): m/z 204 (M+H)⁺ (ES⁺), at 0.91 min

Diisopropyl amine (24.1 mL, 177.3 mmol) was dissolved in THF (100 mL),cooled to −78° C. under N₂, and 1.6 M N-Butyl lithium (89.0 mL, 142.0mmol) added dropwise at −78° C. The reaction mixture was stirred at 0°C. for 40 min before addition of EtOAc (9.4 g, 160.4 mmol) at −78° C.and further stirring for 10 min. 1-Benzoylazepan-4-one (18 g, 88.6 mmol)in THF (160 mL) was then added at −78° C. and the resulting mixturestirred at rt for 1 h. The reaction mixture was quenched with asaturated solution of NH₄Cl, diluted with water (500 mL), extracted withEtOAc (3×200 mL), and combined organics dried (Na₂SO₄) and the solventswere removed in vacuo. The crude residue was purified by columnchromatography (Normal phase, Neutral silica gel, 60-120 mesh, 0 to 25%EtOAc in hexane) to give ethyl 2-(1-benzyl-4-hydroxyazepan-4-yl)acetate(17.5 g, 67.8%) as a yellow gum.

LCMS (Method F): m/z 293 (M+H)⁺ (ES⁺), at 1.60 min

Ethyl 2-(1-benzyl-4-hydroxyazepan-4-yl)acetate (17.5 g, 59.9 mmol) andhydrazine hydrate (100 mL) were stirred at 100° C. for 4 h. The reactionmixture was concentrated in vacuo to give2-(1-benzyl-4-hydroxyazepan-4-yl)acetohydrazide (22 g crude) as a yellowgum, which was taken on directly to the next step.

LCMS (Method K): m/z 278 (M+H)⁺ (ES⁺), at 3.40 min

2-(1-Benzyl-4-hydroxypiperidin-4-yl)acetohydrazide (22.0 g, 79.0 mmol)was dissolved in H₂O (120 mL) and acidified with conc. HCl at 0° C. Tothe reaction mixture was added NaNO₂ (14.0 g, 197.6 mmol) in H₂O (30 mL)at 0° C. and stirring continued at 60° C. for 1 h. The reaction mixturewas basified with 20% NaOH solution, diluted with H₂O (500 mL),extracted with EtOAc (3×200 mL), and combined organics dried (Na₂SO₄)and the solvents were removed in vacuo. The crude product was purifiedby column chromatography (Normal phase, Neutral silica gel, 60-120 mesh,0 to 8% MeOH in DCM) to give8-benzyl-1-oxa-3,8-diazaspiro[4.6]undecan-2-one (8.5 g, 41.4%) as ayellow solid.

LCMS (Method F): m/z 261 (M+H)⁺ (ES⁺), at 1.44 min

To a solution of 8-benzyl-1-oxa-3,8-diazaspiro[4.6]undecan-2-one (8.5 g,32.5 mmol) in MeOH (50 mL) was added 10% Pd/C (2.5 g) and the suspensionstirred at 60° C. for 2 h at 1 atm H₂ pressure. The reaction mixture wasfiltered through celite and the solvents were removed in vacuo to give1-oxa-3,8-diazaspiro[4.6]undecan-2-one, Intermediate 80 (5.3 g, 94.8%)as a light yellow solid.

The data for the title compound, are in Table 2

Route 11 Typical Procedure for the Preparation of Piperidines asExemplified by the Preparation of Intermediate 82,4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one

To a solution of NaH (8.96 g, 50% in mineral oil, 186.9 mmol) in THF(160 mL), triethylphosphonoacetate (20.5 mL, 102.7 mmol) was added at 0°C. After stirring for 1 h at 0° C., picolinaldehyde (10.00 g, 93.4 mmol)was slowly added at 0° C. and the reaction mixture was stirred at rt for2 h. The reaction mixture was quenched with H₂O (10 mL) and the aqueouslayer was extracted with EtOAc (3×100 mL). The organic layers werecombined, dried (Na₂SO₄) and the solvents were removed in vacuo. Thecrude residue was purified by flash column chromatography [normal phase,silica gel (100-200 mesh), gradient 10% to 30% EtOAc in hexane] to giveethyl (E)-3-(pyridin-2-yl)acrylate (7.90 g, 49%) as a liquid.

m/z (ES⁺): 178 (M+H)⁺

To a solution of ethyl (E)-3-(pyridin-2-yl)acrylate (7.9 g, 23.0 mmol)in MeOH (100 mL), 10% Pd/C (0.80 g, 50% wet) was added and the reactionmixture was stirred under H₂ (1 atm) at rt for 16 h. The reactionmixture was filtered through a pad of celite, thoroughly washed withMeOH and the solvents were removed in vacuo to give ethyl3-(pyridin-2-yl)propanoate (7.8 g, 98%) as a liquid.

m/z (ES⁺): 179 (M+H)⁺

To a solution ethyl 3-(pyridin-2-yl)propanoate (2.90 g, 16.2 mmol) inTHF (60 mL), LiHMDS (1 M, 48.6 mL, 48.6 mmol) was slowly added at −78°C. and stirred for 30 min, followed by addition of1-benzylpiperidin-4-one (3.10 g, 16.2 mmol) at −78° C. and the reactionmixture was stirred at −78° C. for 4 h. After completion, the reactionmixture was quenched with sat NH₄Cl solution (30 mL) and the aqueouslayer was extracted with EtOAc (3×30 mL). The organic layers werecombined, dried (Na₂SO₄) and the solvents were removed in vacuo. Thecrude residue was purified by flash column chromatography [normal phase,silica gel (100-200 mesh), gradient 10% to 30% EtOAc in hexane] to giveethyl 2-(1-benzyl-4-hydroxypiperidin-4-yl)-3-(pyridin-2-yl)propanoate(2.80 g, 50%) as a liquid.

m/z (ES⁺): 369 (M+H)⁺

To a solution of ethyl2-(1-benzyl-4-hydroxypiperidin-4-yl)-3-(pyridin-2-yl)propanoate (2.80 g,7.61 mmol) in MeOH:THF (1:1, 30 mL), LiOH.H₂O (1.28 g, 30.4 mmol) inwater (10 mL), was added at rt and the reaction mixture was stirred for16 h. The reaction mixture was acidified with glacial acetic acid andextracted with EtOAc (3×20 mL). The organic layers were combined andwashed with brine, dried (Na₂SO₄) and the solvents were removed in vacuoto give 2-(1-benzyl-4-hydroxypiperidin-4-yl)-3-(pyridin-2-yl)propanoicacid (2.16 g, 84%) as a pale yellow solid.

m/z (ES⁺): 339 (M+H)⁺

To a solution of2-(1-benzyl-4-hydroxypiperidin-4-yl)-3-(pyridin-2-yl)propanoic acid(1.70 g, 5.11 mmol) in toluene (30 mL) was added DPPA (1.32 mL, 6.13mmol) and Et₃N (0.84 mL, 6.13 mmol) and the reaction mixture was heatedat 80° C. for 16 h. The reaction mixture was cooled to rt and thesolvents were removed in vacuo. The residue was purified by flash columnchromatography [normal phase, silica gel (100-200 mesh), gradient 1% to30% EtOAc in hexane] to give8-benzyl-4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one(1.25 g, 56%) as a white solid.

m/z (ES⁺): 338 (M+H)⁺

To a solution of8-benzyl-4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one(0.80 g, 2.37 mmol) in MeOH (40 mL), after degassing under N₂, 10%Pd(OH)₂ on charcoal (0.15 g, 50% wet) was added. The reaction mixturewas stirred under H₂ (1 atm) at rt for 16 h. After completion, thereaction mixture was filtered through a pad of celite, thoroughly washedwith MeOH and the solvents were removed in vacuo to give4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one,Intermediate 83 (0.58 g, 98%) as a liquid.

The data for the title compound, are in Table 2

Route 12 Typical Procedure for the Preparation of Piperidines asExemplified by the Preparation of Intermediate 88,4-(2,2,2-trifluoroethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one

Diisopropyl amine (12.8 g, 126.98 mmol) was dissolved in THF (100 mL)and cooled to −78° C. under nitrogen. n-Butyl lithium (79.3 mL, 126.98mmol, 1.6 M in THF) was added dropwise and the reaction mixture wasstirred at −78° C. for 1 h. Ethyl 4,4,4-trifluorobutanoate (16.2 g,95.23 mmol) was added over 30 min then the reaction mixture was stirredat −78° C. for 1 h. N-benzyl piperidone (15 g, 79.36 mmol) was addeddropwise and the reaction mixture was stirred at −78° C. for 30 minutes.The reaction was quenched with a saturated solution of NH₄Cl (200 mL),diluted with water (500 mL) and extracted with EtOAc (3×200 mL), thecombined organic layers were dried (Na₂SO₄) and the solvents wereremoved in vacuo. The residue was purified by column chromatography(Normal phase, Neutral silica gel, 60-120 mesh, 0 to 25% EtOAc inHexane) to give ethyl2-(1-benzyl-4-hydroxypiperidin-4-yl)-4,4,4-trifluorobutanoate (24.0 g,84.2%) as a yellow gum.

LCMS (Method F): m/z 360 (M+H)⁺ (ES⁺), at 1.75 min, UV active

Ethyl 2-(1-benzyl-4-hydroxypiperidin-4-yl)-4,4,4-trifluorobutanoate(24.0 g, 66.85 mmol) and 85% hydrazine hydrate (200 mL) were dissolvedin ethanol (100 mL). The reaction mixture was refluxed and allowed tostir at 100° C. for 72 h. The reaction mixture was concentrated in vacuoto give the crude product of2-(1-benzyl-4-hydroxypiperidin-4-yl)-4,4,4-trifluorobutanehydrazide(28.0 g) as a yellow gum. The crude product was used in the next stepwithout any purification.

LCMS (Method F): m/z 346 (M+H)⁺ (ES⁺), at 1.41 min, UV active

Crude2-(1-benzyl-4-hydroxypiperidin-4-yl)-4,4,4-trifluorobutanehydrazide (28g, 81.1 mmol) was dissolved in water (200 mL), acidified with conc HCland cooled to 0° C. NaNO₂ (16.7 g, 243.2 mmol) in water (50 mL) wasadded at 0° C. and the reaction mixture was allowed to stir at 60° C.for 1 h. The reaction was basified with 20% NaOH solution, diluted withwater (500 mL) and extracted with EtOAc (3×200 mL), the combined organiclayers were dried (Na₂SO₄) and the solvents were removed in vacuo. Theresidue was purified by column chromatography (Normal phase, Neutralsilica gel, 60-120 mesh, 0 to 3.0% MeOH in dichloromethane) to give8-benzyl-4-(2,2,2-trifluoroethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one(1.2 g, 4.5%) as a yellow solid.

LCMS (Method F): m/z 329 (M+H)⁺ (ES⁺), at 1.48 min, UV active

8-Benzyl-4-(2,2,2-trifluoroethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one(1.2 g, 3.65 mmol) was dissolved in methanol (30 mL). Pd/C (300 mg, 10%Pd/C 50% moisture) was added and the reaction mixture was stirred undera hydrogen atmosphere (1 atm) at 50° C. for 2 h. The reaction mixturewas filtered through celite and the solvents were removed in vacuo. Thecrude product was triturated with diethyl ether to give4-(2,2,2-trifluoroethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one,Intermediate 88 (0.75 g, 88.2%) as a yellow solid

The data for the title compound are in Table 2.

Route 13 Typical Procedure for the Preparation of Piperidines, asExemplified by the Preparation of Intermediate 88,1-propyl-1,2,8-triazaspiro[4.5]decan-3-one.HCl

Sodium hydride in mineral oil (60%, 11.9 g, 297 mmol) was dissolved inDMF (200 mL) and methyl 2-(dimethoxyphosphoryl)acetate (52.0 g, 286mmol) was added drop wise at 0° C. The reaction mixture was stirred at0° C. for 20 min then tert-butyl 4-oxopiperidine-1-carboxylate (45.5 g,228 mmol) in DMF (100 mL) was added drop wise at 0° C. The reactionmixture was stirred at rt for 2 h, then diluted with ice water (20 mL),filtered and the solvents were removed in vacuo to give tert-butyl4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (42.5 g, 72.9%) asa yellow solid.

LCMS (Method F): m/z 256 (M+H)⁺ (ES⁺), at 2.47 min, UV active

tert-Butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (3.0 g,11.8 mmol) was dissolved in EtOH (20 mL) and hydrazine hydrate (1.1 mL,23.5 mmol) was added and the reaction mixture was stirred at 80° C. for8 h. The reaction mixture was partitioned between water (150 mL) andEtOAc (120 mL), aqueous layer was further extracted with EtOAc (2×120mL), organic layers were combined washed with brine (100 mL) and dried(Na₂SO₄). The solvents were removed in vacuo and the residue waspurified by column chromatography (normal silica, mesh size: 60-120,4.0% to 10.0% MeOH in DCM) to give tert-butyl 3-oxo-1, 2,8-triazaspiro[4.5]decane-8-carboxylate (1.78 g, 59.3%) as white solid.

LCMS (Method F): m/z 256 (M+H)⁺ (ES⁺), at 1.70 min, UV inactive

tert-Butyl 3-oxo-1,2,8-triazaspiro[4.5]decane-8-carboxylate (500 mg,1.96 mmol), was dissolved in MeOH (10 mL). Propionaldehyde (0.2 mL, 2.16mmol) and triethylamine (0.8 mL, 5.88 mmol) were added, the reactionmixture was stirred at 45° C. for 3 h. NaCNBH₃ (370 mg, 5.88 mmol) wasadded portion wise and the reaction mixture was stirred at rt for 17 h.The solvents were removed in vacuo and the residue was partitionedbetween H₂O (100 mL) and EtOAc (80 mL), aqueous layer was extracted withEtOAc (2×80 mL), the organic layers were combined, washed with brine(100 mL) and dried (Na₂SO₄). The solvents were removed in vacuo and theresidue was purified by triturating with Hexane (3×3 mL) to givetert-butyl 1-propyl-3-oxo-1,2,8-triazaspiro[4.5]decane-8-carboxylate(560 mg, 96.2%) as a yellow gum.

LCMS (Method E): m/z 298 (M+H)⁺ (ES⁺), at 3.72 min, UV inactive

tert-Butyl 1-propyl-3-oxo-1,2,8-triazaspiro[4.5]decane-8-carboxylate(610 mg, 2.05 mmol) was dissolved in 1,4-dioxane (3 mL) and 4.0M HCl indioxane (5 mL) was added drop wise, the reaction mixture was stirred at25° C. for 16 h. The solvents were removed in vacuo and the residue waspurified by triturating with Et₂O (3×3 mL) to give1-propyl-1,2,8-triazaspiro[4.5]decan-3-one. HCl, Intermediate 88 (470mg, 98.3%) as an off white solid.

The data for the title compound are in Table 2

General Synthetic Procedures: Route a Typical Procedure for thePreparation of Piperidines Via NaCNBH₃ Reductive Amination asExemplified by the Preparation of Example 2-2, ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

2,8-Diazaspiro[4.5]decan-3-one.HCl (0.40 g, 1.78 mmol) was dissolved inMeOH (3 mL) and treated with K₂CO₃ (0.49 g, 3.55 mmol) in a minimum ofwater to de-salt. The mixture was concentrated in vacuo. The residue andethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.35 g, 1.78 mmol)were dissolved in MeOH (8 mL) and zinc chloride (0.73 g, 5.33 mmol) wasadded. The reaction mixture was stirred at 50° C., under a nitrogenatmosphere, for 2 h then cooled to rt and NaCNBH₃ (0.23 g, 3.55 mmol)was added. The reaction mixture was stirred at 50° C. under nitrogen for16 h. The reaction mixture was cooled to rt and treated with sat. NaHCO₃sol., the organic solvent was removed in vacuo and the aqueous layer wasextracted with DCM (2×10 mL) the organic layers were combined and washedwith brine (10 mL) and dried by passing through a Biotage PhaseSeparator cartridge. The solvents were removed in vacuo, and the residuewas purified by column chromatography (normal phase, [Interchimcartridge Puriflash column 15 silica HP-silica 15μ 40 G, 30 mL per min,gradient 0% to 10% MeOH in DCM]) to give ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylateExample 2-2 Isomer 1 (16 mg, 2.5%) as an off-white solid and ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylateExample 2-2 Isomer 2 (10 mg, 1.7%) as an off-white solid.

The data for Isomers 1 and 2 are in Table 3.

Route b Typical Procedure for the Preparation of Piperidines via NaCNBH₃Reductive Amination as Exemplified by the Preparation of Example 2-8,ethyl 3-(1-ethyl-3-oxo-2,8-diazaspiro[4.5]decan-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

1-Ethyl-2,8-diazaspiro[4.5]decan-3-one.HCl (0.1 g, 0.55 mmol), ethyl3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.2 g, 0.60 mmol), Et₃N(0.38 mL, 2.74 mmol) and ZnCl₂ (0.04 g, 0.03 mmol) were dissolved inMeOH (5 mL) under N₂ and stirred at 60° C. for 16 h. Reaction mixturecooled to 0° C. and NaCNBH₃ (0.17 g, 2.74 mmol) was added portion wise,the reaction mixture was stirred under N₂ at 60° C. for 16 h. Thesolvents were removed in vacuo and the residue was partitioned betweenwater (50 mL) and EtOAc (30 mL), the aqueous layer was further extractedwith EtOAc (2×30 mL); the organic layers were combined and washed withbrine, then dried (Na₂SO₄).

The solvents were removed in vacuo and the residue was purified bypreparative reversed phase HPLC (Durashell, 250×21.2 mm, 5 um, 13 mL permin, gradient 30% to 100% (over 28 min), then 100% (3 min) Acetonitrilein 50% Acetonitrile/water (0.1% Ammonia)) to give ethyl3-(1-ethyl-3-oxo-2,8-diazaspiro[4.5]decan-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylateExample 2-8 Isomer 1 (0.03 g, 15.1%) as a colourless solid and ethyl3-(1-ethyl-3-oxo-2,8-diazaspiro[4.5]decan-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate Example 2-8 Isomer 2 (0.006 g, 3.1%) as acolourless solid.

The data for both isomers are in Table 3.

Route c Typical Procedure for the Preparation of Piperidines Via SodiumTriacetoxyborohydride Reductive Amination in DMF as Exemplified by thePreparation of Example 3-2, ethyl5-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate

1-Oxa-3,8-diazaspiro[4.5]decan-2-one hydrochloride (0.10 g, 0.52 mmol)and ethyl 5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate (0.10 g, 0.51mmol) were mixed in DMF (5 mL) at rt. DIPEA (0.18 mL, 1.0 mmol) and AcOH(0.044 mL, 0.77 mmol) were added, followed by STAB (0.32 g, 1.5 mmol).The reaction mixture was stirred under nitrogen at 45° C. for 3 d and at60° C. for 1 d, the solvents were removed in vacuo. The residue waspurified by column chromatography (normal phase, [Biotage SNAP cartridgeKP-sil 25 g, 40-63 μm, 60 Å, 30 mL per min, gradient 0% to 10% Solvent Ain DCM over 10 column volumes, then isocratic 10% Solvent A in DCM for 5column volumes, where solvent A is 10% of (7 M NH₃/MeOH) in MeOH]) togive a mixture of diastereomers. This mixture was purified bypreparative reversed phase HPLC (Phenomenex Gemini-NX 5 μm C18 110A Axiacolumn, 100×30 mm, eluted with 15 to 55% MeCN/Solvent B over 14.4 min at30 mL/min [where solvent B is 0.2% of (28% NH₃/H₂O) in H₂O] andcollecting fractions by monitoring at 205 nm) to give ethyl5-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylateExample 3-2 Isomer 1 (0.074 g, 43%) as a colourless solid and ethyl5-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylateExample 3-2 Isomer 2 (0.023 g, 13%) as a colourless solid.

The data for Isomers 1 and 2 are in Table 3.

Route d Typical Procedure for the Preparation of Piperidines Via SodiumTriacetoxyborohydride Reductive Amination as Exemplified by thePreparation of Example 5-2, prop-2-yn-1-yl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate

2,8-Diazaspiro[4.5]decan-3-one (0.12 g, 0.75 mmol) and prop-2-yn-1-yl3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate (0.17 g, 0.75 mmol) weredissolved in DCE (7.5 mL) at rt and titanium isopropoxide (0.66 mL, 2.25mmol) was added. The reaction mixture was heated to reflux under N₂ for16 h then cooled to rt. STAB (0.80 g, 3.75 mmol) was added, the reactionmixture again heated to reflux for 16 h then cooled to rt. The reactionmixture was quenched with the addition of sat. NaHCO₃ sol. (10 mL),diluted with DCM (10 mL) then filtered through a pad of celite. Thelayers were separated and the aqueous layer was extracted with DCM (4×20mL). The organic layers were combined and washed with brine, then dried(MgSO₄). The solvents were removed in vacuo, and the residue waspurified by column chromatography (normal phase, [Biotage SNAP cartridgeKP-sil 25 g, 40-63 μm, 60 Å, 27 mL per min, gradient 1% to 10% MeOH inDCM]) to give an inseparable mixture of diastereomers This mixture waspurified by preparative reversed phase HPLC (Phenomenex Gemini-NX 5 μmC18 110A Axia column, 100×30 mm, eluting with 15 to 35% MeCN/Solvent Bover 14.4 min at 30 mL/min [where solvent B is 0.2% of (28% NH₃/H₂O) inH₂O] and collecting fractions by monitoring at 205 nm) to giveprop-2-yn-1-yl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylateExample 5-2 Isomer (0.02 g, 7%) as a colourless solid and prop-2-yn-1-yl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylateExample 5-2 Isomer 2 (0.03 g, 11%) as a colourless solid.

The data for both isomers are in Table 3.

Route e Typical Procedure for the Preparation of Piperidines Via SodiumTriacetoxyborohydride Reductive Amination, Boc-Deprotection andEthylcarbamate Formation as Exemplified by the Preparation of Example5-1, ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate

2,8-Diazaspiro[4.5]decan-3-one (0.15 g, 1.0 mmol) and tert-butyl3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate (0.25 g, 0.1.05 mmol) weredissolved in DCE (10.0 mL) at rt and titanium isopropoxide (0.89 mL, 3.0mmol) was added. The reaction mixture was stirred overnight at refluxunder N₂, then cooled to room temperature. STAB (1.06 g, 5.0 mmol) wasadded, the reaction mixture again heated to reflux, maintained overnightand then cooled to room temperature. The reaction mixture was quenchedwith the addition of sat. NaHCO₃ sol. (10 mL), diluted with DCM (10 mL)then filtered through a pad of celite. The layers were separated and theaqueous layer was extracted with DCM (4×20 mL). The organic layers werecombined and washed with brine, then dried (MgSO₄). The solvents wereremoved in vacuo to give crude tea-butyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylatewhich was used without any purification.

LCMS (Method C): m/z 378 (M+H)⁺ (ES⁺), at 1.54 min, UV active.

tert-Butyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate(0.38 g, 1.0 mmol assumed) was dissolved in DCM (10 mL), 4.0 M HCl in1,4-dioxane (1.25 mL, 5.0 mmol) was added and the reaction mixturestirred at rt for 18 h. The volatiles were removed in vacuo, the residuedissolved in DCM (10 mL), Et₃N (0.70 mL, 5.0 mmol) and ethylchloroformate (143 μL, 1.50 mmol) added dropwise and the solutionstirred at rt for 18 h. The mixture was then poured into sat. NaHCO₃sol. (20 mL), extracted with DCM (4×20 mL), the organic layers werecombined and washed with brine, then dried (MgSO₄). The solvents wereremoved in vacuo and the residue was purified by column chromatography(normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 27mL per min, gradient 1% to 10% MeOH in DCM]) to give an inseparablemixture of diastereomers. This mixture was purified by preparativereversed phase HPLC (Phenomenex Gemini-NX 5 μm C18 110A Axia column,100×30 mm, eluting with 20 to 30% MeCN/Solvent B over 14.4 min at 30mL/min [where solvent B is 0.2% of (28% NH₃/H₂O) in H₂O] and collectingfractions by monitoring at 205 nm) to give ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylateExample 5-1 Isomer 1 (0.02 g, 6%) as a colourless solid and ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylateExample 5-1 Isomer 2 (0.01 g, 3%) as a colourless solid.

The data for both isomers are in Table 3.

Route f Typical Procedure for the Preparation of Piperidines Via NaCNBH₃Reductive Amination, Boc-Deprotection and Ethylcarbamate Formation asExemplified by the Preparation of Example 7-1, ethyl6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.2.1]octane-3-carboxylate

1-Oxa-3,8-diazaspiro[4.5]decan-2-one. HCl (0.15 g, 0.76 mmol) wasdissolved in MeOH (3 mL) and treated with K₂CO₃ (0.11 g, 0.76 mmol) in aminimum of water to desalt. The solvents were removed in vacuo and theresidue was dissolved in MeOH (8 mL) andethyl-6-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (0.15 g, 0.76 mmol)and ZnCl₂ (0.31 g, 2.28 mmol) were added. The reaction mixture wasstirred at 50° C. under a N₂ for 2 h then cooled to rt and NaCNBH₃ (0.10g, 1.52 mmol) was added. The reaction mixture was stirred at 50° C.under a N₂ for 16 h then cooled to rt and quenched with sat. NaHCO₃ sol.(10 mL). The solvents were removed in vacuo and the aqueous layer waswashed with DCM (2×10 mL) the organic layers were combined and washedwith brine, then dried by passing through a Biotage Phase Separatorcartridge. The solvents were removed in vacuo and the residue waspurified by column chromatography (normal phase, [Biotage SNAP cartridgeKP-sil 10 g, 40-63 μm, 60 Å, 12 mL per min, gradient 0% to 10% MeOH inDCM]) to tert-butyl6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.2.1]octane-3-carboxylate(6.0 mg, 2.2%) as a colourless gum

LCMS (Method D): m/z 366 (M+H)⁺ (ES⁺), at 1.76 min, UV inactive.

tert-Butyl6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.2.1]octane-3-carboxylate(6.0 mg, 0.016 mmol) was diluted in 4.0 M HCl in 1,4-dioxane (3 mL) andstirred at rt under a N₂ for 16 h. The solvents were removed in vacuoand the residue was dissolved in DCM (4 mL) and cooled to 0° C. underN₂, Et₃N (5 mg, 0.048 mmol) and ethyl chloroformate (4 mg, 0.032 mmol)were added and the reaction mixture was stirred at rt under N₂ for 16 h.The reaction mixture was diluted with DCM (10 mL) and washed with sat.NaHCO₃ sol. (20 mL), the aqueous layer was extracted with DCM (2×15 mL),the organic layers were combined and washed with brine, then dried bypassing through a Biotage phase separator cartridge. The solvents wereremoved in vacuo and the residue was purified by preparative reversedphase HPLC (Phenomenex Gemini-NX 5 μm C18 110 A Axia column, 100×30 mm,eluting with 20 to 50% MeCN/Solvent B over 14.4 min at 30 mL/min [wheresolvent B is 0.2% of (28% NH₃/H₂O) in H₂O] and collecting fractions bymonitoring at 205 nm) to give ethyl6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.2.1]octane-3-carboxylateExample 7-1 Isomer 1 (0.84 mg, 15%) as a colourless gum.

The data for this compound are in Table 3.

Route g Typical Procedure for the Preparation of Piperidines Via NaCNBH₃Reductive Amination as Exemplified by the Preparation of Example 2-23,ethyl3-(2-oxo-4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

To a solution of4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one (0.10 g,0.41 mmol) and ethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.80g, 0.41 mmol) in MeOH (5 mL), ZnCl₂ (0.17 g, 1.21 mmol) was added. Thereaction mixture was stirred at 60° C., under a N₂ atmosphere, for 6 hthen cooled to rt and NaCNBH₃ (0.08 g, 1.21 mmol) was added. Thereaction mixture was stirred at 60° C. under nitrogen for 16 h. Thereaction mixture was cooled to rt, the solvent was removed in vacuo andthe residue partitioned between sat. NaHCO₃ sol. (10 mL) and DCM (10mL), the aqueous layer was further washed with DCM (2×10 mL). Theorganic layers were combined and washed with brine, dried (Na₂SO₄) andthe solvents were removed in vacuo. The residue was purified by columnchromatography (normal phase, silica gel (100-200 mesh), gradient 2% to5% MeOH in DCM] to giveethyl-3-(2-oxo-4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylateas a mixture of diastereomers, Example 2-23 (32 mg, 20%) as a whitesolid.

The data for example 2-23 is in Table 3.

Route h Procedure for the Preparation of Example 2-24, ethyl(3-endo)-3-(2-hydroxy-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

A solution of ethyl(3-endo)-3-[4-(2-ethoxy-2-oxoethyl)-4-(nitromethyl)piperidin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate(2.00 g, 4.87 mmol) in anhydrous MeOH (30 mL) was divided equallybetween 4×20 mL microwave vials. The solutions were degassed withnitrogen and then 10% palladium on carbon (0.13 mg, 1.21 mmol) andammonium formate (1.54 g, 24.20 mmol) were added. The vials were sealedand stirred at rt for 4 h. The four reaction mixtures were combined andfiltered through a celite pad under nitrogen, and the solvents wereremoved in vacuo. The residue was purified by preparative reversed phaseHPLC [Gemini-NX C18, 5μ, 100×30 mm, 30 mL per min, 5-35% MeCN/Water+0.2%Ammonia (28% Ammonia Solution) to give Example 2-24,8-[8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-3-oxo-2,8-diazaspiro[4.5]decan-2-olate(0.90 g, 52.5%) as a white solid.

The data for the title compound is in Table 3.

Route l Typical Procedure for the Preparation of Piperidines ViaN-Alkylation as Exemplified by the Preparation of Example 2-25, ethyl3-(3-oxo-2-propyl-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

Ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate(0.20 g, 0.59 mmol) was dissolved in DMF (5.0 mL). NaH (60%) (0.071 g,1.78 mmol) was added at 0° C. and the reaction mixture stirred at 0° C.for 30 min. 1-Bromopropane (0.11 g, 0.89 mmol) was added and thereaction mixture stirred at rt for 1 h. The reaction mixture wasquenched with the addition of water (20 mL) and extracted with EtOAc(150 mL), the aqueous layer was further extracted with EtOAc (2×15 mL);the organic layers were combined and washed with brine, then dried(Na₂SO₄). The solvents were removed in vacuo, and the residue waspurified by preparative reversed phase HPLC [X-Bridge, 150×19 mm, 5 μm,12 mL per min, isocratic 29% (for 20 min), then 100% (4 min) MeCN in 50%MeCN/water (0.1%, Ammonia)] to give ethyl3-(3-oxo-2-propyl-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,Example 2-25 (14.5 mg, 6.5%) as a colourless solid.

The data for the title compound are in Table 3.

Route j Typical Procedure for the Preparation of Piperidines ViaCarbamate Formation, as Exemplified by the Preparation of Example 2-30,(1,1-²H₂)ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

4-Nitrophenyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate(100 mg, 0.24 mmol) was dissolved in anhydrous DMF (3 mL) and 60% sodiumhydride suspension in mineral oil (47 mg, 1.18 mmol) was added. Thereaction mixture was stirred at rt under nitrogen for 10 min.Ethanol-1,1-d₂ (57 mg, 1.18 mmol) was added and the reaction mixture wasstirred overnight at rt under nitrogen. Water (1 mL) was added to thereaction mixture and the solvents were removed in vacuo. The residue waspartitioned between DCM (10 mL) and sat. aqueous NaHCO₃ (10 mL), theaqueous layer was extracted with DCM (2×10 mL). The combined organicswere dried by passing through a Biotage Phase Separator cartridge andthe solvents were removed in vacuo. The residue was purified by columnchromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63μm, 60 Å, 12 mL per min, gradient 0% to 10% MeOH in DCM]) to give(1,1-²H₂)ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,Example 2-30 Isomer 1 (11 mg, 14%) as a pale yellow gum and(1,1-²H₂)ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,Example 2-30 Isomer 2 (18 mg, 23%) as a pale yellow gum.

The data for both isomers are in Table 3.

Route k Typical Procedure for the Preparation of Piperidines Via SodiumTriacetoxyborohydride Reductive Amination in DMF as Exemplified by thePreparation of Example 3-1, ethyl5-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate

To a solution of ethyl 5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate(6.70 g, 34 mmol) and 2,8-diazaspiro[4.5]decan-3-onel (5.24 g, 34 mmol)in DMF (30 mL) was added HOAc (2.9 mL, 51 mmol) under nitrogen, thereaction mixture was stirred at rt for 20 min. Na(OAc)₃BH (21.60 g, 102mmol) was added and the reaction was stirred at 45° C. for 3 d. Then thereaction mixture was warmed to 60° C. and stirred for another 24 h. Thesolvent was removed in vacuo and the residue was dissolved in water (20mL) and basified with sat. NaHCO₃. The aqueous layer was concentrated todryness and the resulting white solid was diluted with DCM (100 mL). Thesuspension was stirred at rt for 30 min, filtered and the filter cakewas washed with DCM (4×25 mL). The organic layers were combined and thesolvent was removed in vacuo. The residue was purified by preparativereversed phase HPLC (Instrument: Gilson, Column: Xbridge 21.2*250 mmC18, 10 um; Mobile Phase: A: water (10 mMol/L NH₄HCO₃) B: CAN); Flowrate (ml/min): 25.00) to give the two racemic isomers of ethyl5-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate.Which were further purified by chiral SFC (Column: OJ-H, 4.6*250 mm;Co-solvent: MeOH (0.1% NH₄OH); column temperature: 40; CO₂ flow rate:2.55) to give ethyl5-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate,Example 3-1 Isomer 1 (0.78 g, 6.9%) as a colourless solid, ethyl5-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate,Example 3-1 Isomer 2 (1.20 g, 10.5%) as a colourless solid, ethyl5-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate,Example 3-1 Isomer 3 (0.45 g, 3.9%) as a colourless solid and ethyl5-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate,Example 3-1 Isomer 4 (1.30 g, 11.4%) as a colourless solid.

The data for all four isomers are in Table 3.

Route l Typical Procedure for the Preparation of Piperidines Via NaCNBH₃Reductive Amination as Exemplified by the Preparation of Example 3-3,ethyl5-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate

Ethyl 5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate (0.077 g, 0.39 mmol)and 4-ethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one (0.070 g, 0.39 mmol)were dissolved in DCM (3.9 mL). Titanium (IV) isopropoxide (0.35 mL,1.17 mmol) was added and the reaction mixture was stirred at rt undernitrogen for 3 h. NaCNBH₃ (0.049 g, 0.78 mmol) was added and the mixturestirred at rt under nitrogen overnight. The reaction mixture waspartitioned between water (10 mL) and DCM (10 mL) and the solution waspassed through a celite pad to remove solids. The filtrate layers wereseparated and the aqueous phase was extracted with DCM (3×25 mL). Theorganic phases were combined and washed with sat. NaHCO₃ sol. (25 mL)and dried by passing through a Biotage Phase Separator cartridge. Thesolvents were removed in vacuo, and the residue was purified by columnchromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63μm, 60 Å, 10 mL per min, gradient 0% to 10% MeOH in DCM]) to give amixture of diastereomers of ethyl5-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate.This mixture of diastereomers was further purified by preparativereversed phase HPLC (Phenomenex Gemini-NX 5 μm C18 110A Axia column,100×30 mm, eluting with 20 to 50% MeCN/Solvent B over 12.5 min at 30mL/min [where solvent B is 0.2% of (28% NH₃/H₂O) in H₂O] and collectingfractions by monitoring at 205 nm) to give ethyl5-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate,Example 3-3 Isomer 1 (0.021 g, 14.8%) as a colourless solid and ethyl5-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate,Example 3-3 Isomer 2 (0.022 g, 15.5%) as a colourless solid.

The data for isomer 2 are in Table 2.

Route m Typical Procedure for the Preparation of Piperidines Via NaBH₄Reductive Amination as Exemplified by the Preparation of Example 8-1,ethyl6-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.1.1]heptane-3-carboxylate

2,8-Diazaspiro[4.5]decan-3-one (0.11 g, 0.72 mmol) and ethyl6-oxo-3-azabicyclo[3.1.1]heptane-3-carboxylate (0.12 g, 0.65 mmol) weredissolved in DCM (6.5 mL). Titanium (IV) isopropoxide (0.35 mL, 1.17mmol) was added and the reaction mixture was stirred at rt undernitrogen overnight. The reaction mixture was cooled to −78° C. and MeOH(15 mL) was added, the reaction mixture was stirred for 15 min at −78°C. NaBH₄ (0.18 g, 5.20 mmol) was added and the reaction mixture wasstirred at −78° C. for 1 h then at rt under nitrogen overnight. Thereaction mixture was treated with NaOH (1 M, 10 mL) and stirred for 30min. The precipitate was collected by filtration, washed with MeOH (3×20mL) and the solvents were removed in vacuo. The residue was purified bycolumn chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25g, 40-63 μm, 60 Å, 25 mL per min, gradient 0% to 10% MeOH in DCM]) togive a mixture of diastereomers of ethyl6-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.1.1]heptane-3-carboxylate.The mixture of diastereomers was purified by preparative reversed phaseHPLC (Phenomenex Gemini-NX 5 μm C18 110A Axia column, 100×30 mm, elutingwith 15 to 50% MeCN/Solvent B over 12.5 min at 30 mL/min [where solventB is 0.2% of (28% NH₃/H₂O) in H₂O] and collecting fractions bymonitoring at 205 nm) to give ethyl6-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.1.1]heptane-3-carboxylate,Example 8-1 Isomer 1 (0.006 g, 2.9%) as a colourless solid and ethyl6-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.1.1]heptane-3-carboxylate,Example 8-1 Isomer 2 (0.040 g, 19.2%) as a colourless solid.

The data for the title compound are in Table 2

Route n Typical Procedure for the Preparation of Azepanes Via NaCNBH₃Reductive Amination as Exemplified by the Preparation of Example 9-1,ethyl3-(3-oxo-2,8-diazaspiro[4.6]undec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

tert-Butyl 3-oxo-2,8-diazaspiro[4.6]undecane-8-carboxylate (0.398 g,1.49 mmol) was added to 4.0 M HCl in 1,4-dioxane (8 mL) and stirred atrt under N₂ for 16 h. The solvents were removed in vacuo to give2,8-diazaspiro[4.6]undecan-3-one hydrochloride (0.303 g, 100%) which wasused without further purification. A portion of2,8-diazaspiro[4.6]undecan-3-one hydrochloride (0.179 g, 0.74 mmol) wasdissolved in MeOH (5 mL) and potassium carbonate (0.102 g, 0.74 mmol)dissolved in a minimum of water was added to desalt the amine. Thesolvents were removed in vacuo and the residue was dissolved in MeOH (8mL) and ethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.14 g,0.74 mmol) and ZnCl₂ (0.30 g, 2.29 mmol) were added. The reactionmixture was stirred at 50° C. under N₂ for 2 h then cooled to rt andNaCNBH₃ (0.09 g, 1.49 mmol) was added. The reaction mixture was stirredat 50° C. under a N₂ for 16 h then cooled to rt and quenched with sat.NaHCO₃ sol. (10 mL). The methanol was removed in vacuo and the resultingsolution was washed with DCM (2×10 mL) the organic layers were combinedand washed with brine, then dried by passing through a Biotage PhaseSeparator cartridge. The solvents were removed in vacuo and the residuewas purified by column chromatography (normal phase, [Biotage SNAPcartridge KP-sil 10 g, 40-63 μm, 60 Å, 1 2 mL per min, gradient 2% to10% MeOH in DCM]) to give ethyl3-(3-oxo-2,8-diazaspiro[4.6]undec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,Example 9-1 Isomer 1 (0.034 g, 13.0%) as a yellow gum, and ethyl3-(3-oxo-2,8-diazaspiro[4.6]undec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylateExample 9-1 Isomer 2 (0.02 g, 0.9%) as a yellow gum.

The data for these compound are in Table 3.

Route o Typical Procedure for the Preparation of Azepanes Via NaCNBH₃Reductive Amination as Exemplified by the Preparation of Example 9-2,ethyl3-(2-oxo-1-oxa-3,8-diazaspiro[4.6]undec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

1-Oxa-3,8-diazaspiro[4.6]undecan-2-one hydrochloride (5.3 g, 31.0 mmol),ethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (6.1 g, 31.0 mmol),Et₃N (13.0 mL, 93.0 mmol), 4 A molecular sieves (2.0 g) and ZnCl₂ (1.0 Min diethyl ether, 1.5 mL, 1.5 mmol) were dissolved in MeOH (160 mL) andstirred at reflux under N₂ for 8 h. The reaction mixture was cooled to0° C. and NaCNBH₃ (5.8 g, 93.0 mmol) was added portion wise, thereaction mixture was stirred at reflux under N₂ for 48 h. The reactionmixture was filtered through celite and the solvents were removed invacuo. The residue was partitioned between H₂O (500 mL) and EtOAc (150mL), and the aqueous layer was further extracted with EtOAc (2×150 mL).The combined organic layers were dried over Na₂SO₄ and the solvents wereremoved in vacuo. The residue was purified by column chromatography(Normal phase, Neutral silica gel, 100-200 mesh, 0 to 8% MeOH in DCM) togive two isomers of ethyl3-(2-oxo-1-oxa-3,8-diazaspiro[4.6]undec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,major isomer (3.00 g, 27.6%) as a colourless gum and minor isomer (0.40g, 3.7%) as a colourless gum. The major isomer (100 mg) was furtherpurified by chiral preparative HPLC [(Chiral PAK IB (250×20) mm 5μ, 13.0ml/min using an isocratic method in 0.1% DEA in n-hexane:IPA:MeOH(19:1:1) for 50 min] to give ethyl3-(2-oxo-1-oxa-3,8-diazaspiro[4.6]undec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,Example 9-2 Isomer 1 (45.0 mg, 45.0%) as colourless gum, ethyl3-(2-oxo-1-oxa-3,8-diazaspiro[4.6]undec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,Example 9-2 Isomer 2 (40.0 mg, 40.0%) as a colourless gum. The minorisomer (150 mg) was further purified by chiral preparative HPLC [(ChiralPAK IC SFC (250×21) mm 15.0 mL/min using an isocratic method in 0.1% DEAin n-hexane:IPA:THF:MeOH (14:1:1:4) for 33 min] to give ethyl3-(2-oxo-1-oxa-3,8-diazaspiro[4.6]undec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,Example 9-2 Isomer 3 (50.0 mg, 33.3%) as a colourless gum and ethyl3-(2-oxo-1-oxa-3,8-diazaspiro[4.6]undec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,Example 9-2 Isomer 4 (52.4 mg, 34.9%) as a colourless gum.

The data for the title compound are in Table 3.

TABLE 2 Starting Materials and Intermediates Intermediate Route NameData 1 2,8-diazaspiro[4.5]decan-3- Commercially available, one.HCl CAS:945892-88-6 2 Route 1 and 1-methyl-2,8- LCMS (Method F): m/z 169 (M +H)⁺ intermediates diazaspiro[4.5]decan-3- (ES⁺), at 4.65 min, UVinactive 38 and 47 one.HCl 3 Route 1 and 1-ethyl-2,8- LCMS (Method F):m/z 183 (M + H)⁺ intermediates diazaspiro[4.5]decan-3- (ES⁺), at 5.55min, UV inactive 38 and 48 one.HCl 4 Route 1 and 1-propyl-2,8- LCMS(Method F): m/z 197 (M + H)⁺ intermediates diazaspiro[4.5]decan-3-(ES⁺), at 5.31 min, UV inactive 38 and 49 one.HCl 5 Route 1 and1-benzyl-2,8- LCMS (Method F): m/z 245 (M + H)⁺ intermediatesdiazaspiro[4.5]decan-3- (ES⁺), at 1.47 min, UV active 38 and 50 one.HCl6 Route 2 and 6-fluoro-2,8- LCMS (Method D): m/z 173 (M + H)⁺intermediates diazaspiro[4.5]decan-3- (ES⁺), at 0.13 min, UV inactive 39and 46 one.HCl 7 Route 3 and 2-ethyl-2,8- LCMS (Method H): m/z 183 (M +H)⁺ intermediates diazaspiro[4.5]decan-3- (ES⁺), at 5.36 min, UVinactive 38 and 46 one.HCl 8 1-oxa-3,8- Commercially available,diazaspiro[4.5]decan-2- CAS: 2052-96-0 one.HCl 9 Route 3 and4-methyl-1-oxa-3,8- LCMS (Method G): m/z 171 (M + H)⁺ intermediatesdiazaspiro[4.5]decan-2-one (ES⁺), at 4.31 min, UV inactive 37 and 51 10Route 3 and 4-ethyl-1-oxa-3,8- LCMS (Method G): m/z 185 (M + H)⁺intermediates diazaspiro[4.5]decan-2-one (ES⁺), at 3.27 min, UV inactive37 and 52 11 Route 3 and 4-(propan-2-yl)-1-oxa-3,8- LCMS (Method G): m/z199 (M + H)⁺ intermediates diazaspiro[4.5]decan-2-one (ES⁺), at 3.68min, UV inactive 37 and 53 12 Route 3 and 4,4-dimethyl-1-oxa-3,8- LCMS(Method G): m/z 185 (M + H)⁺ intermediates diazaspiro[4.5]decan-2-one(ES⁺), at 1.90 min, UV active 37 and 54 131,3,8-triazaspiro[4.5]decan-2- Commercially available, one CAS:561314-52-1 14 2-azabicyclo[2.2.1]heptane- Commercially available,2-carboxylic acid, 5-oxo-, CAS: 198835-06-2 1,1-dimethylethyl ester 15Route 6 and 2-azabicyclo[2.2.1]heptane- ¹H NMR: (400 MHz, DMSO-d₆) δ:intermediates 2-carboxylic acid, 5-oxo-, 1.08-1.23 (m, 3 H), 1.90-2.03(m, 2 14 and 42 ethyl ester H), 2.07 (dd, J = 17.5, 4.0 Hz, 1 H), 2.26(d, J = 17.5 Hz, 1 H), 2.78- 2.83 (m, 1 H), 3.06-3.20 (m, 1 H),3.35-3.48 (m, 1 H), 3.95-4.09 (m, 2 H), 4.45 (s, 1 H) 16 Route 5 andmethyl 3-oxo-8- LCMS (Method C): m/z 184 (M + H)⁺ intermediatesazabicyclo[3.2.1]octane-8- (ES⁺), at 0.72 min, UV inactive 18 and 41carboxylate 17 ethyl 3-oxo-8- Commercially available,azabicyclo[3.2.1]octane-8- CAS: 32499-64-2 carboxylate 18nortropinone.HCl Commercially available, CAS: 25602-68-0 19 Route 5 and2-fluoroethyl 3-oxo-8- LCMS (Method C): m/z 216 (M + H)⁺ intermediatesazabicyclo[3.2.1]octane-8- (ES⁺), at 0.82 min, UV inactive 18 and 43carboxylate 20 Route 5 and prop-2-yn-1-yl 3-oxo-8- LCMS (Method C): m/z208 (M + H)⁺ intermediates azabicyclo[3.2.1]octane-8- (ES⁺), at 0.84min, UV inactive 18 and 44 carboxylate 21 Route 5 and but-2-yn-1-yl3-oxo-8- LCMS (Method C): m/z 222 (M + H)⁺ intermediatesazabicyclo[3.2.1]octane-8- (ES⁺), at 1.00 min, UV inactive 18 and 45carboxylate 22 Route 6 and ethyl 2-fluoro-3-oxo-8- ¹H NMR: (400 MHz,CDCl₃) δ: 1.27- intermediates azabicyclo[3.2.1]octane-8- 1.34 (m, 3 H),1.42-1.55 (m, 1 H), 36 and 42 carboxylate 1.60-1.71 (m, 1 H), 1.89-2.19(m, 2 H), 2.33-2.51 (m, 1 H), 2.63-3.11 (m, 1 H), 4.18-4.27 (m, 2 H),4.29- 4.50 (m, 1 H), 4.50-4.70 (m, 1 H), 4.70-4.97 (m, 1 H) 23 Route 5and 8-butanoyl-8- LCMS (Method C): m/z 196 (M + H)⁺ intermediatesazabicyclo[3.2.1]octan-3-one (ES⁺), at 0.74 min, UV active 18 and 40 24tert-butyl 5-oxo-2- Commercially available, azabicyclo[2.2.2]octane-2-CAS: 617714-22-4 carboxylate 25 Route 6 and ethyl 5-oxo-2- LCMS (MethodC): m/z 198 (M + H)⁺ intermediates azabicyclo[2.2.2]octane-2- (ES⁺), at0.84 min, UV active 24 and 42 carboxylate 26 3-Boc-3-azabicyclo[3.2.1]Commercially available, octan-8-one CAS: 637301-19-0 27 Route 6 and3-azabicyclo[3.2.1]octane-3- ¹H NMR: (400 MHz, DMSO-d₆) δ: intermediatescarboxylic acid, 8-oxo-, ethyl 1.19 (t, J = 7.0 Hz, 3 H), 1.46-1.68 26and 42 ester (m, 2 H), 1.78-1.93 (m, 2 H), 2.10- 2.24 (m., 2 H),3.11-3.26 (m, 2 H), 3.97-4.23 (m, 4 H) 28 tert-butyl 3-oxo-9-Commercially available, azabicyclo[3.3.1]nonane-9- CAS: 512822-27-4carboxylate 29 Route 6 and ethyl 3-oxo-9- LCMS (Method C): m/z 212 (M +H)⁺ intermediates azabicyclo[3.3.1]nonane-9- (ES⁺), at 2.06 min, UVactive 38 and 42 carboxylate 30 Route 6 and prop-2-yn-1-yl 3-oxo-9- LCMS(Method C): m/z 222 (M + H)⁺ intermediates azabicyclo[3.3.1]nonane-9-(ES⁺), at 1.95 min, UV active 38 and 44 carboxylate 31 Route 6 andbut-2-yn-1-yl 3-oxo-9- LCMS (Method C): m/z 237 (M + H)⁺ intermediatesazabicyclo[3.3.1]nonane-9- (ES⁺), at 2.47 min, UV active 38 and 45carboxylate 32 tert-butyl 3-oxo-6- Commercially available,azabicyclo[3.2.1]octane-6- CAS: 359779-74-1 carboxylate 33 Route 6 andmethyl 3-oxo-6- ¹H NMR: (400 MHz, DMSO-d₆) δ: intermediatesazabicyclo[3.2.1]octane-6- 1.94-2.06 (m, 2 H), 2.24-2.34 (m, 1 38 and 41carboxylate H), 2.34-2.44 (m, 1 H), 2.57 (dd, J = 4.5, 2.0 Hz, 1 H),2.59-2.70 (m, 2 H), 3.09-3.22 (m, 1 H), 3.22-3.31 (m, 1 H), 3.52-3.58(m, 3 H), 4.12- 4.20 (m, 1 H) 34 Route 6 and ethyl 3-oxo-6- ¹H NMR: (400MHz, DMSO-d₆) δ: intermediates azabicyclo[3.2.1]octane-6- 1.14 (td, J =7.0, 4.0 Hz, 3 H), 1.94- 32 and 42 carboxylate 2.05 (m, 2 H), 2.24-2.34(m, 1 H), 2.46 (d, J = 2.5 Hz, 1 H), 2.57 (dd, J = 4.5, 2.0 Hz, 1 H),2.59-2.71 (m, 2 H), 3.11-3.19 (m, 1 H), 3.24-3.31 (m, 1 H), 3.92-4.04(m, 2 H), 4.12- 4.19 (m, 1 H) 35 6-oxo-3-aza-bicyclo[3.2.1] Commerciallyavailable, octane-3-carboxylic acid tert- CAS: 1369502-46-4 butyl ester36 8-azabicyclo[3.2.1]octane-8- Commercially available, carboxylic acid,2-fluoro-3- CAS: 1404196-37-7 oxo-, 1,1-dimethylethyl ester 37N-benzyl-4-piperidinone Commercially available, CAS: 3612-20-2 38tert-butyl 4-oxopiperidine-1- Commercially available, carboxylate CAS:79099-07-3 39 tert-butyl-3-fluoro-4-oxo- Commercially available,piperidine-1-carboxylate CAS: 211108-50-8 40 n-butyryl chlorideCommercially available, CAS: 141-75-3 41 methyl chloroformateCommercially available, CAS: 79-22-1 42 ethyl chloroformate Commerciallyavailable, CAS: 541-41-3 43 2-fluoroethyl chloroformate Commerciallyavailable, CAS: 462-27-1 44 prop-2-yn-1-yl chloroformate Commerciallyavailable, CAS: 68622-10-6 45 but-2-yn-1-yl chloroformate Commerciallyavailable, CAS: 202591-85-3 46 nitromethane Commercially available, CAS:75-52-5 47 nitroethane Commercially available, CAS: 79-24-3 481-nitropropane Commercially available, CAS: 108-03-2 49 1-nitrobutaneCommercially available, CAS: 627-05-4 50 2-phenyl-1-nitroethaneCommercially available, CAS: 6125-24-2 51 2-bromopropanoic acid ethylCommercially available, ester CAS: 535-11-5 52 2-bromobutanoic acidethyl Commercially available, ester CAS: 533-68-6 532-bromo-3-methylbutyric acid Commercially available, ethyl ester CAS:609-12-1 54 2-bromo-2-methylpropionic Commercially available, acid ethylester CAS: 600-00-0 55 4-nitrophenyl chloroformate Commerciallyavailable, CAS: 7693-46-1 56 Route 5 and 4-nitrophenyl 3-oxo-8- LCMS(Method D): m/z 291 (M + H)⁺ intermediates azabicyclo[3.2.1]octane-8-(ES⁺), at 1.67 min, UV active 18 and 55 carboxylate 572,8-diazaspiro[4.5]decan-3- Commercially available, one CAS: 561314-57-658 Route 7 and 4-nitrophenyl 3-(3-oxo-2,8- LCMS (Method D): m/z 429 (M +H)⁺ intermediates diazaspiro[4.5]dec-8-yl)-8- (ES⁺), at 1.81 min and1.86 min, 56 and 57 azabicyclo[3.2.1]octane-8- carboxylate 59ethanol-1,1,2,2,2-d₅ Commercially available CAS: 1859-08-1 60ethanol-1,1-d₂ Commercially available CAS: 1859-09-2 61 ethanol-2,2,2-d₃Commercially available CAS: 1759-87-1 62 tert-butyl 6-oxo-3-Commercially available: azabicyclo[3.1.1]heptane-3- CAS: 1305208-01-8carboxylate 63 Route 6 and ethyl 6-oxo-3- ¹H NMR: (400 MHz, CDCl₃) δ:1.11- intermediates azabicyclo[3.1.1]heptane-3- 1.23 (m, 3 H), 1.69-1.76(m, 1 H), 42 and 62 carboxylate 2.03-2.13 (m, 1 H), 2.94-3.11 (m, 2 H),3.80-3.90 (m, 2 H), 3.93-4.12 (m, 4 H). 64 ethyl(3-endo)-3-[4-(2-ethoxy- LCMS (Method D): m/z 412 (M + H)⁺2-oxoethyl)-4- (ES⁺), at 2.25 min (nitromethyl)piperidin-1-yl]-8-azabicyclo[3.2.1]octane-8- carboxylate 65 1-tert- Commerciallyavailable: Butoxycarbonylperhydroazepin-4-one CAS: 188975-88-4 66 Route3 and tert-butyl 3-oxo-2,8- ¹H NMR: (400 MHz, DMSO) δ: 1.37intermediates diazaspiro[4.6]undecane-8- (s, 9 H), 1.44-1.67 (m, 6 H),1.90- 46 and 65 carboxylate 2.05 (m, 2 H), 2.97 (s, 2 H), 3.21- 3.29 (m,4 H), 7.49 (br. s., 1 H) 67 Route 8 and 1-benzyl-1,2,8- LCMS (Method G):m/z 246 (M + H)⁺ intermediate 38 triazaspiro[4.5]decan-3-one (ES⁺) at4.35 min UV active 68 Route 6 and propan-2-yl 3-oxo-8- LCMS (Method J):m/z 212 (M + H)⁺ intermediates azabicyclo[3.2.1]octane-8- (ES⁺) at 4.00min UV active 69 and 70 carboxylate 69 tert-butyl 3-oxo-8- Commerciallyavailable azabicyclo[3.2.1]octane-8- CAS: 185099-67-6 carboxylate 70isopropylchloroformate Commercially available CAS: 108-23-6 71 Route 6and S-methyl 3-oxo-8- LCMS (Method J): m/z 200 (M + H)⁺ intermediatesazabicyclo[3.2.1]octane-8- (ES⁺) at 3.63 min UV active 69 and 72carbothioate 72 S-methyl Commercially available carbonochloridothioateCAS: 18369-83-0 73 1-bromopropane Commercially available CAS: 106-94-574 2-iodopropane Commercially available CAS: 75-30-9 75 1-bromo-2-methylpropane Commercially available CAS: 78-77-3 76 1-Bromo-2-methoxy ethaneCommercially available CAS: 6482-24-2 77 Route 9 and S-ethyl 3-oxo-8- ¹HNMR: (400 MHz, DMSO) δ: 1.33 Intermediates azabicyclo[3.2.1]octane-8-(t, J = 7.2 Hz, 3 H), 1.60-1.66 (m, 2 69, 78, and 79 carbothioate H),2.00-2.06 (m, 2 H), 2.62-2.66 (m, 2 H), 2.86-2.90 (m, 2 H), 3.11- 3.15(m, 2 H), 4.55-4.60 (m, 2 H) 78 carbonyldiimidazole Commerciallyavailable CAS: 530-62-1 79 Ethanethiol Commercially available CAS:75-08-1 80 Route 10 and 1-oxa-3,8- LCMS (Method J): m/z 171 (M + H)⁺intermediate 81 diazaspiro[4.6]undecan-2- (ES⁺), at 2.49 min one 81azepan-4-one HCl salt Commercially available: CAS: 50492-22-3 82 Route11 and 4-(pyridin-2-ylmethyl)-1-oxa- LCMS (Method o): m/z 248 (M + H)⁺Intermediate 83 3,8-diazaspiro[4.5]decan-2- (ES⁺) at 5.23 min UV activeone 83 pyridine-2-carboxaldehyde Commerically available CAS: 1121-60-484 cyclopropyl methyl bromide Commerically available CAS: 7051-34-5 85ethyl 4,4,4-trifluorobutanoate Commercially available, CAS: 317-26-6 86Route 12 and 4-(2,2,2-trifluoroethyl)-1-oxa- LCMS (Method H): m/z 239(M + H)⁺ intermediates 3,8-diazaspiro[4.5]decan-2- (ES⁺) at 2.79 min UVinactive 37 and 85 one 87 propionaldehyde Commercially available CAS:123-38-6 88 Route 13 and 1-propyl-1,2,8- LCMS (Method K): m/z 198 (M +H)⁺ intermediates triazaspiro[4.5]decan-3-one. (ES⁺), at 2.55 min, UVinactive 38 and 87 HCl

TABLE 3 Synthetic LCMS Ex. No. Name Intermediate method ¹H NMR MethodLCMS data 1-1 Isomer 1: ethyl 5-(2-oxo-1- 1 and 15 a (400 MHz, DMSO-d₆)δ: 1.13 (m,, 3 H), 1.34-1.49 (m, E m/z 324 (M + H)⁺ (ES+), atoxa-3,8-diazaspiro[4.5]dec- 2 H), 1.49-1.59 (m, 1 H), 1.71 (s, 3 H),1.68 (s, 2 H), 1.73 min, UV inactive 8-yl)-2- 2.20-2.25 (m, 1 H),2.30-2.44 (m, 3 H), 2.62-2.72 azabicyclo[2.2.1]heptane-2- (m, 2 H), 2.78(t, J = 9.8 Hz, 1 H), 3.13 (s, 1 H), 3.19 carboxylate (s, 2 H),3.87-4.03 (m, 2 H), 4.05 (s, 1 H), 7.45 (s, 1 H) 2-1 Isomer 1: methyl3-(3-oxo- 1 and 16 a (400 MHz, DMSO-d₆) δ: 1.52 (m, 4 H), 1.67-1.93 (m,E m/z 322 (M + H)⁺ (ES+), at 2,8-diazaspiro[4.5]dec-8-yl)- 8 H), 1.96(s, 2 H), 2.14-2.24 (m, 1 H), 2.24-2.43 2.05 min, UV inactive8-azabicyclo[3.2.1]octane-8- (m, 4 H), 2.97 (s, 2 H), 3.55 (s, 3 H),4.04 (d, J = 6.3 carboxylate Hz, 2 H), 7.47 (s, 1 H) 2-1 Isomer 2:methyl 3-(3-oxo- 1 and 16 a (400 MHz, DMSO-d₆) δ: 1.32-1.54 (m, 6 H),1.54- E m/z 322 (M + H)⁺ (ES+), at 2,8-diazaspiro[4.5]dec-8-yl)- 1.67(m, 4 H), 1.71-1.89 (m, 2 H), 1.94 (s, 2 H), 2.19- 2.14 min, UV inactive8-azabicyclo[3.2.1]octane-8- 2.46 (m, 4 H), 2.59-2.84 (m, 1 H), 2.95 (s,2 H), carboxylate 3.56 (s, 3 H), 4.04-4.20 (m, 2 H), 7.46 (s, 1 H) 2-2Isomer 1: ethyl 3-(3-oxo-2,8- 1 and 17 a (400 MHz, DMSO-d₆) δ: 1.14 (t,J = 7.0 Hz, 3 H), 1.42- B m/z 336 (M + H)⁺ (ES+), atdiazaspiro[4.5]dec-8-yl)-8- 1.59 (m, 4 H), 1.67-1.92 (m, 9 H), 1.96 (s,2 H), 2.26 min, UV inactive azabicyclo[3.2.1]octane-8- 2.10-2.45 (m, 4H), 2.97 (s, 2 H), 3.90-4.09 (m, 4 carboxylate H), 7.49 (br. s., 1 H)2-2 Isomer 2: ethyl 3-(3-oxo-2,8- 1 and 17 a (400 MHz, DMSO-d₆) δ: 1.15(t, J = 7.0 Hz, 3 H), 1.31- B m/z 336 (M + H)⁺ (ES+), atdiazaspiro[4.5]dec-8-yl)-8- 1.56 (m, 6 H), 1.56-1.72 (m, 4 H), 1.72-1.91(m, 2 2.14 min, UV inactive azabicyclo[3.2.1]octane-8- H), 1.94 (s, 2H), 2.20-2.44 (m, 4 H), 2.70-2.75 (m, carboxylate 1 H), 2.95 (s, 2 H),4.01 (q, J = 7.0 Hz, 2 H), 4.08- 4.17 (m, 2 H), 7.44 (s, 1 H) 2-3 Isomer1: 2-fluoroethyl 3-(3- 1 and 19 a (400 MHz, DMSO-d₆) δ: 1.53-1.59 (m, 4H), 1.66- E m/z 354 (M + H)⁺ (ES+), at oxo-2,8-diazaspiro[4.5]dec- 1.95(m, 8 H), 1.97 (s, 2 H), 2.10-2.45 (m, 5 H), 2.98 2.34 min, UV inactive8-yl)-8- (s, 2 H), 3.95-4.13 (m, 2 H), 4.13-4.38 (m, 2 H),azabicyclo[3.2.1]octane-8- 4.51 (t, J = 4.0 Hz, 1 H), 4.63 (t, J = 4.0Hz, 1 H), 7.47 carboxylate (s, 1 H) 2-3 Isomer 2: 2-fluoroethyl 3-(3- 1and 19 a (400 MHz, DMSO-d₆) δ: 1.35-1.55 (m, 6 H), 1.55- E m/z 354 (M +H)⁺ (ES+), at oxo-2,8-diazaspiro[4.5]dec- 1.74 (m, 4 H), 1.81-1.92 (m, 2H), 1.95 (s, 2 H), 2.20- 2.29 min, UV inactive 8-yl)-8- 2.46 (m, 4 H),2.68-2.85 (m, 1 H), 2.95 (s, 2 H), azabicyclo[3.2.1]octane-8- 4.02-4.23(m, 3 H), 4.23-4.35 (m, 1 H), 4.51 (t, J = carboxylate 4.0 Hz, 1 H),4.63 (t, J = 4.0 Hz, 1 H), 7.46 (s, 1 H) 2-4 Isomer 1: prop-2-yn-1-yl 3-1 and 20 a (400 MHz, DMSO-d₆) δ: 1.41-1.58 (m, 4 H), 1.58- E m/z 346(M + H)⁺ (ES+), at (3-oxo-2,8- 1.70 (m, 1 H), 1.70-1.93 (m, 7 H), 1.96(s, 2 H), 2.17- 2.49 min, UV inactive diazaspiro[4.5]dec-8-yl)-8- 2.43(m, 5 H), 2.97 (s, 2 H), 3.48 (t, J = 2.34 Hz, 1azabicyclo[3.2.1]octane-8- H), 4.01-4.16 (m, 2 H), 4.64 (d, J = 2.34 Hz,2 H), 7.47 carboxylate (s, 1 H) 2-4 Isomer 2: prop-2-yn-1-yl 3- 1 and 20a (400 MHz, DMSO-d₆) δ: 1.46 (t, J = 5.5 Hz, 6 H), 1.55- E m/z 346 (M +H)⁺ (ES+), at (3-oxo-2,8- 1.73 (m, 4 H), 1.81-1.92 (m, 2 H), 1.92-1.98(m, 2 2.46 min, UV inactive diazaspiro[4.5]dec-8-yl)-8- H), 2.23-2.45(m, 4 H), 2.71-2.80 (m, 1 H), 2.90- azabicyclo[3.2.1]octane-8- 3.00 (m,2 H), 3.44-3.52 (m, 1 H), 4.03-4.19 (m, 2 carboxylate H), 4.65 (dd, J =2.5, 1.5 Hz, 2 H), 7.45 (s, 1 H) 2-5 Isomer 1: but-2-yn-1-yl 3-(3- 1 and21 a (400 MHz, DMSO-d₆) δ: 1.35-1.58 (m, 4 H), 1.58- E m/z 360 (M + H)⁺(ES+), at oxo-2,8-diazaspiro[4.5]dec- 1.71 (m, 1 H), 1.71-1.94 (m, 10H), 1.96 (s, 2 H), 2.80 min, UV inactive 8-yl)-8- 2.14-2.56 (m., 5 H),2.96 (s, 2 H), 4.03-4.14 (m, 2 azabicyclo[3.2.1]octane-8- H), 4.55-4.65(m, 2 H), 7.47 (s, 1 H) carboxylate 2-5 Isomer 2: but-2-yn-1-yl 3-(3- 1and 21 a (400 MHz, DMSO-d₆) δ: 1.36-1.55 (m, 6 H), 1.55- E m/z 360 (M +H)⁺ (ES+), at oxo-2,8-diazaspiro[4.5]dec- 1.72 (m, 4 H), 1.79 (t, J =2.5 Hz, 3 H), 1.81-1.92 (m, 2.75 min, UV inactive 8-yl)-8- 2 H), 1.94(s, 2 H), 2.22-2.45 (m, 4 H), 2.73-2.80 azabicyclo[3.2.1]octane-8- (m, 1H), 2.95 (s, 2 H), 4.03-4.20 (m, 2 H), 4.61 (q, J = carboxylate 2.5 Hz,2 H), 7.45 (s, 1 H) 2-6 Isomer 2: 8-(8-butanoyl-8- 1 and 23 a (400 MHz,DMSO-d₆) δ: 0.86 (t, J = 7.5 Hz, 3 H), 1.35- E m/z 334 (M + H)⁺ (ES+),at azabicyclo[3.2.1]oct-3-yl)- 1.55 (m, 8 H), 1.55-1.78 (m, 5 H),1.80-1.92 (m, 1 2.17 min, UV inactive 2,8-diazaspiro[4.5]decan-3- H),1.92-2.02 (m, 2 H), 2.09-2.29 (m, 2 H), 2.29- one 2.46 (m, 4 H),2.70-2.89 (m, 1 H), 2.95 (s, 2 H), 4.12- 4.31 (m, 1 H), 4.36-4.58 (m, 1H), 7.46 (s, 1 H) 2-7 Isomer 1: ethyl 3-(1-methyl- 2 and 17 a (400 MHz,DMSO-d₆) δ: 0.96 (d, J = 6.5 Hz, 3 H), 1.14 E m/z 350 (M + H)⁺ (ES+), at3-oxo-2,8- (t, J = 7.0 Hz, 3 H), 1.34-1.50 (m, 3 H), 1.67-1.81 2.50 min,UV inactive diazaspiro[4.5]dec-8-yl)-8- (m, 4 H), 1.81-2.05 (m, 5 H),2.13-2.27 (m, 1 H), azabicyclo[3.2.1]octane-8- 2.36-2.47 (m, 2 H),2.52-2.61 (m, 1 H), 2.67-2.85 carboxylate (m, 1H), 3.13-3.28 (m, 3 H),3.95-4.08 (m, 4 H), 7.57 (s, 1 H) 2-7 Isomer 2: ethyl 3-(1-methyl- 2 and17 a (400 MHz, DMSO-d₆) δ: 0.94 (d, J = 6.5 Hz, 3 H), 1.15 E m/z 350(M + H)⁺ (ES+), at 3-oxo-2,8- (t, J = 7.0 Hz, 3 H), 1.24-1.37 (m, 1 H),1.37-1.54 2.72 min, UV inactive diazaspiro[4.5]dec-8-yl)-8- (m, 4 H),1.58-1.72 (m, 4 H), 1.74-1.86 (m, 2 H), 1.90 azabicyclo[3.2.1]octane-8-(d, J = 16.40 Hz, 1 H), 2.06 (d, J = 16.40 Hz, 1 H), carboxylate2.09-2.28 (m, 2 H), 2.51-2.64 (m, 2 H), 2.66-2.88 (m, 1 H), 3.19 (q, J =6.38 Hz, 2 H), 3.95-4.06 (m, 2 H), 4.07-4.22 (m, 2 H), 7.55 (s, 1 H) 2-8Isomer 1: ethyl 3-(1-ethyl-3- 3 and 17 b (400 MHz, DMSO-d₆) δ: 0.89 (t,J = 7.5 Hz, 3 H), 1.10- F m/z 364 (M + H)⁺ (ES+), atoxo-2,8-diazaspiro[4.5]dec- 1.27 (m, 4 H), 1.37-1.76 (m, 6 H), 1.71-2.14(m, 9 1.60 min, UV inactive 8-yl)-8- H), 2.18-2.35 (m, 1 H), 2.54-2.59(m, 2 H), 2.62- azabicyclo[3.2.1]octane-8- 2.83 (m, 2 H), 2.91-3.00 (m,1 H), 3.98-4.09 (m, 4 carboxylate H), 7.88 (s, 1 H) 2-8 Isomer 2: ethyl3-(1-ethyl-3- 3 and 17 b (400 MHz, DMSO-d₆) δ: 0.88 (t, J = 7.5 Hz, 3H), 1.17 F m/z 364 (M + H)⁺ (ES+), at oxo-2,8-diazaspiro[4.5]dec- (t, J= 7.0 Hz, 4 H), 1.31-1.55 (m, 7 H), 1.57-1.70 1.61 min, UV inactive8-yl)-8- (m, 4 H), 1.77-1.98 (m, 3 H), 2.01-2.24 (m, 3 H),azabicyclo[3.2.1]octane-8- 2.55-2.62 (m, 2 H), 2.65-2.80 (m, 1 H),2.88-3.00 carboxylate (m, 1 H), 3.98-4.08 (m, 2 H), 4.09-4.17 (m, 2 H),7.85 (s, 1 H) 2-9 Isomer 1: ethyl 3-(3-oxo-1- 4 and 17 b (400 MHz,DMSO-d₆) δ: 0.88 (t, J = 7.0 Hz, 3 H), 1.10- F m/z 378 (M + H)⁺ (ES+),at propyl-2,8- 1.26 (m, 5 H), 1.29-1.59 (m, 6 H), 1.67-2.12 (m, 12 1.63min, UV inactive diazaspiro[4.5]dec-8-yl)-8- H), 2.16-2.25 (m, 1 H),2.56-2.85 (m, 2 H), 3.00- azabicyclo[3.2.1]octane-8- 3.11 (m, 1 H),3.94-4.12 (m, 4 H), 7.85 (s, 1 H) carboxylate 2-9 Isomer 2: ethyl3-(3-oxo-1- 4 and 17 b (400 MHz, DMSO-d₆) δ: 0.87 (t, J = 7.0 Hz, 3 H),1.17 F m/z 378 (M + H)⁺ (ES+), at propyl-2,8- (t, J = 7.0 Hz, 5 H),1.28-1.55 (m, 8 H), 1.57-1.70 1.64 min, UV inactivediazaspiro[4.5]dec-8-yl)-8- (m, 4 H), 1.79-1.96 (m, 3 H), 2.01-2.23 (m,3 H), azabicyclo[3.2.1]octane-8- 2.53-2.60 (m, 2 H), 2.65-2.80 (m, 1 H),3.04 (d, J = carboxylate 7.5 Hz, 1 H), 3.99-4.09 (m, 2 H), 4.10-4.21 (m,2 H), 7.82 (s, 1 H) 2-10 Isomer 1: ethyl 3-(1-benzyl- 5 and 17 b (400MHz, DMSO-d₆) δ: 1.18 (t, J = 7.0 Hz, 3 H), 1.35- H m/z 426 (M + H)⁺(ES+), at 3-oxo-2,8- 1.54 (m, 5 H), 1.55-1.70 (m, 6 H), 1.76-2.01 (m, 39.35 min, UV active diazaspiro[4.5]dec-8-yl)-8- H), 2.09-2.26 (m, 3 H),2.55-2.64 (m, 2 H), 2.66- azabicyclo[3.2.1]octane-8- 2.87 (m, 2 H),3.38-3.45 (m, 1 H), 3.98-4.09 (m, 2 carboxylate H), 4.11-4.19 (m, 2 H),7.14-7.24 (m, 3 H), 7.26- 7.34 (m, 2 H), 7.40 (s, 1 H) 2-10 Isomer 2:ethyl 3-(1-benzyl- 5 and 17 b (400 MHz, MeOD-d₄) δ: 1.20-1.40 (m, 4 H),1.60- H m/z 426 (M + H)⁺ (ES+), at 3-oxo-2,8- 1.78 (m, 5 H), 1.79-2.00(m, 5 H), 2.13-2.34 (m, 5 9.76 min, UV activediazaspiro[4.5]dec-8-yl)-8- H), 2.34-2.45 (m, 1 H), 2.62 (dd, J = 13.5,10.5 Hz, 1 azabicyclo[3.2.1]octane-8- H), 2.79-3.01 (m, 3 H), 3.58 (dd,J = 10.0, 4.5 Hz, 1 carboxylate H), 4.07-4.19 (m, 2 H), 4.20-4.31 (m, 2H), 7.19- 7.37 (m, 5 H), NH not observed 2-11 Isomer 1: ethyl2-fluoro-3-(3- 1 and 22 a (400 MHz, DMSO-d₆) δ: 1.06-1.20 (m, 3 H), 1.50(s, E m/z 354 (M + H)⁺ (ES+), at oxo-2,8-diazaspiro[4.5]dec- 6 H),1.53-1.57 (m, 1 H), 1.57-1.69 (m, 1 H), 1.69- 2.32 min, UV inactive8-yl)-8- 1.93 (m, 1 H), 1.93-2.09 (m, 3 H), 2.33-2.45 (m, 4azabicyclo[3.2.1]octane-8- H), 2.53-2.58 (m, 1 H), 2.98 (s, 2 H), 3.99(q, J = 7.0 carboxylate Hz, 2 H), 4.09-4.22 (m, 1 H), 4.29 (dd, J =17.0, 8.0 Hz, 1 H), 4.54 (d, J = 4.5 Hz, 0.5 H), 4.67 (d, J = 4.5 Hz,0.5 H), 7.47 (s, 1 H) 2-11 Isomer 2: ethyl 2-fluoro-3-(3- 1 and 22 a(400 MHz, DMSO-d₆) δ: 1.08-1.18 (m 3 H), 1.39- E m/z 354 (M + H)⁺ (ES+),at oxo-2,8-diazaspiro[4.5]dec- 1.52 (m, 4 H), 1.53-1.65 (m, 3 H),1.66-1.82 (m, 3 2.08 min, UV inactive 8-yl)-8- H), 1.95 (s, 2 H),2.32-2.48 (m, 4 H), 2.59-2.69 (m, azabicyclo[3.2.1]octane-8- 1 H), 2.96(s, 2 H), 3.94-4.06 (m, 2 H), 4.12-4.25 carboxylate (m, 1 H), 4.25-4.44(m, 1 H), 4.62-4.75 (m, 0.5 H), 4.75-4.85 (m, 0.5 H), 7.46 (s, 1 H) 2-12Isomer 1: ethyl 3-(6-fluoro-3- 6 and 17 a (400 MHz, DMSO-d₆) δ:1.10-1.17 (m, 3 H), 1.41- E m/z 354 (M + H)⁺ (ES+), atoxo-2,8-diazaspiro[4.5]dec- 1.57 (m, 2 H), 1.57-1.67 (m, 1 H), 1.67-1.84(m, 6 0.25 min, UV inactive 8-yl)-8- H), 1.84-1.95 (m, 2 H), 1.97-2.16(m, 2 H), 2.18- azabicyclo[3.2.1]octane-8- 2.30 (m, 2 H), 2.88-3.05 (m,1 H), 3.10-3.23 (m, 1 carboxylate H), 3.26-3.30 (m, 1 H), 3.92-4.08 (m,4 H), 4.08- 4.21 (m, 1 H), 4.32-4.62 (m, 1 H), 7.59 (s, 1 H) 2-12 Isomer2: ethyl 3-(6-fluoro-3- 6 and 17 a (400 MHz, DMSO-d₆) δ: 1.15 (t, J =7.0 Hz, 3 H), 1.38- E m/z 354 (M + H)⁺ (ES+), atoxo-2,8-diazaspiro[4.5]dec- 1.52 (m, 3 H), 1.53-1.74 (m 5 H), 1.75-1.89(m, 2 2.17 min, UV inactive 8-yl)-8- H), 1.98 (d, J = 17.0 Hz, 1 H),2.13 (d, J = 17.0 Hz, 1 azabicyclo[3.2.1]octane-8- H), 2.24-2.45 (m, 2H), 2.50-2.65 (m, 2 H), 2.72- carboxylate 2.86 (m, 1 H), 2.90 (d, J =10.0 Hz, 1 H), 3.26 (d, J = 10.0 Hz, 1 H), 3.94-4.07 (m, 2 H), 4.07-4.17(m, 2 H), 4.33-4.41 (m, 0.5 H), 4.43-4.54 (m, 0.5 H), 7.57 (s, 1 H) 2-13Isomer 2: ethyl 3-(2-ethyl-3- 7 and 17 b (400 MHz, DMSO-d₆) δ: 1.00 (t,J = 7.0 Hz, 3 H), 1.17 F m/z 364 (M + H)⁺ (ES+), atoxo-2,8-diazaspiro[4.5]dec- (t, J = 7.0 Hz, 3 H), 1.42-1.61 (m, 4 H),1.71-1.98 1.58 min, UV inactive 8-yl)-8- (m, 8 H), 2.09 (s, 2 H),2.18-2.27 (m, 1 H), 2.28- azabicyclo[3.2.1]octane-8- 2.45 (m, 3 H), 3.12(s, 2 H), 3.18 (q, J = 7.0 Hz, 2 H), carboxylate 3.41-3.55 (m, 1 H),3.95-4.17 (m, 4 H) 2-14 Isomer 1: ethyl 3-(2-oxo-1- 8 and 17 a (400 MHz,DMSO-d₆) δ: 1.15 (t, J = 7.0 Hz, 3 H), 1.64- B m/z 338 (M + H)⁺ (ES+),at oxa-3,8-diazaspiro[4.5]dec- 1.93 (m, 13 H), 2.20-2.30 (m, 1 H),2.33-2.46 (m, 2.24 min, UV inactive 8-yl)-8- 3 H), 3.19 (s, 2 H),3.91-4.10 (m, 4 H), 7.42 (s, 1 H) azabicyclo[3.2.1]octane-8- carboxylate2-14 Isomer 2: ethyl 3-(2-oxo-1- 8 and 17 a (400 MHz, DMSO-d₆) δ: 1.15(t, J = 7.0 Hz, 3 H), 1.35- B m/z 338 (M + H)⁺ (ES+), atoxa-3,8-diazaspiro[4.5]dec- 1.55 (m 2 H), 1.56-1.76 (m, 9 H), 1.76-1.86(m, 2 2.23 min, UV inactive 8-yl)-8- H), 2.43 (d, J = 14.0 Hz, 3 H),2.71-2.89 (m, 1 H), azabicyclo[3.2.1]octane-8- 3.17 (s, 2 H), 3.94-4.08(m, 2 H), 4.08-4.19 (m, 2 carboxylate H), 7.41 (s, 1 H) 2-15 Isomer 1:ethyl 3-(4-methyl- 9 and 17 b (400 MHz, DMSO-d₆) δ: 1.02 (d, J = 6.5 Hz,3 H), 1.12- E m/z 352 (m + H)⁺ (ES+) at 2-oxo-1-oxa-3,8- 1.25 (m, 3 H),1.36-1.75 (m, 10 H), 1.78-1.94 (m, 1.69 min, UV inactivediazaspiro[4.5]dec-8-yl)-8- 2 H), 2.23-2.41 (m, 2 H), 2.59-2.72 (m, 2H), 2.76- azabicyclo[3.2.1]octane-8- 2.89 (m, 1 H), 3.41-3.52 (m, 1 H),3.97-4.09 (m, 2 carboxylate H), 4.10-4.23 (m, 2 H), 7.54 (s, 1 H) 2-15Isomer 2: ethyl 3-(4-methyl- 9 and 17 b (400 MHz, DMSO-d₆) δ: 1.03 (d, J= 6.5 Hz, 3 H), 1.17 E m/z 352 (m + H)⁺ (ES+) at 2-oxo-1-oxa-3,8- (t, J= 7.0 Hz, 3 H), 1.53-1.96 (m, 12 H), 2.02-2.21 1.89 min, UV inactivediazaspiro[4.5]dec-8-yl)-8- (m, 2 H), 2.22-2.35 (m, 1 H), 2.76- 2.95 (m,2 H), azabicyclo[3.2.1]octane-8- 3.47 (q, J = 6.5 Hz, 1 H), 3.92-4.17(m, 4 H), 7.55 (s, carboxylate 1 H) 2-16 Isomer 1: ethyl 3-(4-ethyl-2-10 and 17 b (400 MHz, DMSO-d₆) δ: 0.88 (t, J = 7.0 Hz, 3 H), 1.18 E m/z366 (m + H)⁺ (ES+) at oxo-1-oxa-3,8- (t, J = 7.0 Hz, 3 H), 1.21-1.34 (m,1 H), 1.36-1.76 2.19 min, UV inactive diazaspiro[4.5]dec-8-yl)-8- (m, 10H), 1.77-1.93 (m, 2 H), 2.23-2.41 (m, 2 H), azabicyclo[3.2.1]octane-8-2.57-2.70 (m, 2 H), 2.72-2.87 (m, 1 H), 3.14-3.24 carboxylate (m, 2 H),3.98-4.10 (m, 2 H), 4.11-4.20 (m, 2 H), 7.78 (br. s., 1 H) 2-16 Isomer2: ethyl 3-(4-ethyl-2- 10 and 17 b (400 MHz, DMSO-d₆) δ: 0.89 (t, J =7.0 Hz, 3 H), 1.17 E m/z 366 (m + H)⁺ (ES+) at oxo-1-oxa-3,8- (t, J =7.0 Hz, 3 H), 1.21-1.36 (m, 1 H), 1.41-1.56 2.33 min, UV inactivediazaspiro[4.5]dec-8-yl)-8- (m, 1 H), 1.57-1.96 (m, 12 H), 2.00-2.19 (m,2 H), azabicyclo[3.2.1]octane-8- 2.21-2.34 (m, 1 H), 2.81-2.95 (m, 2 H),3.18-3.26 carboxylate (m, 1 H), 3.94-4.16 (m, 4 H), 7.80 (s, 1 H) 2-17Isomer 1: ethyl 3-[2-oxo-4- 11 and 17 b (400 MHz, DMSO-d₆) δ: 0.86 (dd,J = 10.0, 6.5 Hz, 6 E m/z 380 (m + H)⁺ (ES+) at (propan-2-yl)-1-oxa-3,8-H), 1.18 (t, J = 7.0 Hz, 3H), 1.38-1.55 (m, 2 H), 1.56- 2.50 min, UVinactive diazaspiro[4.5]dec-8-yl]-8- 1.91 (m, 11 H), 2.25-2.41 (m, 2 H),2.58-2.71 (m, azabicyclo[3.2.1]octane-8- 2 H), 2.74-2.87 (m, 1 H),3.03-3.11 (m, 1 H), 3.97- carboxylate 4.10 (m, 2 H), 4.11-4.21 (m, 2 H),7.69 (s, 1 H) 2-17 Isomer 2: ethyl 3-[2-oxo-4- 11 and 17 b (400 MHz,DMSO-d₆) δ: 0.87 (dd, J = 11.0, 6.5 Hz, 6 E m/z 380 (m + H)⁺ (ES+) at(propan-2-yl)-1-oxa-3,8- H), 1.12-1.26 (m, 4 H), 1.60-1.94 (m, 13 H),2.04- 2.71 min, UV inactive diazaspiro[4.5]dec-8-yl]-8- 2.18 (m, 2 H),2.23-2.36 (m, 1 H), 2.81-2.98 (m, 2 azabicyclo[3.2.1]octane-8- H),3.05-3.17 (m, 1 H), 3.94-4.17 (m, 4 H), 7.72 carboxylate (br. s., 1 H)2-18 Isomer 1: ethyl 3-(4,4- 12 and 17 b (400 MHz, DMSO-d₆) δ: 1.08 (s,6 H), 1.18 (t, J = 7.0 E m/z 366 (m + H)⁺ (ES+) atdimethyl-2-oxo-1-oxa-3,8- Hz, 3 H), 1.41-1.60 (m, 3 H), 1.60-1.75 (m, 6H), 2.09 min, UV inactive diazaspiro[4.5]dec-8-yl)-8- 1.77-1.94 (m, 2H), 2.15-2.29 (m, 2 H), 2.64-2.84 azabicyclo[3.2.1]octane-8- (m, 4 H),3.97-4.09 (m, 2 H), 4.10-4.21 (m, 2 H), carboxylate 7.48 (s, 1 H) 2-18Isomer 2: ethyl 3-(4,4- 12 and 17 b (400 MHz, DMSO-d₆) δ: 1.10 (s, 6 H),1.17 (t, J = 7.0 E m/z 366 (m + H)⁺ (ES+) at dimethyl-2-oxo-1-oxa-3,8-Hz, 3 H), 1.51-1.65 (m, 2 H), 1.67-2.05 (m, 12 H), 2.24 min, UV inactivediazaspiro[4.5]dec-8-yl)-8- 2.21-2.32 (m, 1 H), 2.96-3.11 (m, 2 H),3.97-4.15 azabicyclo[3.2.1]octane-8- (m, 4 H), 7.50 (br. s., 1 H)carboxylate 2-19 Isomer 1: ethyl 2-fluoro-3-(2- 8 and 22 a (400 MHz,DMSO-d₆) δ: 1.18 (t, J = 7.0 Hz, 3H), 1.36- E m/z 356 (M + H)⁺ (ES+), atoxo-1-oxa-3,8- 2.15 (m, 11H), 2.42-2.63 (m, 6H), 4.03 (q, J = 7.0 2.32min, UV inactive diazaspiro[4.5]dec-8-yl)-8- Hz, 2H), 4.18-4.27 (m, 1H),4.27-4.39 (m, 1H), azabicyclo[3.2.1]octane-8- 4.56-4.73 (m, 1H), 7.49(br s, 1H). carboxylate 2-19 Isomer 2: ethyl 2-fluoro-3-(2- 8 and 22 a(400 MHz, DMSO-d₆) δ: 1.11-1.23 (m, 3H), 1.55- E m/z 356 (M + H)⁺ (ES+),at oxo-1-oxa-3,8- 1.90 (m, 11H), 2.43-2.80 (m, 6H), 4.03 (m, 2H), 4.19-2.03 min, UV inactive diazaspiro[4.5]dec-8-yl)-8- 4.31 (m, 1H),4.32-4.44 (m, 1H), 4.72-4.90 (m, azabicyclo[3.2.1]octane-8- 1H), 7.47(br s, 1H). carboxylate 2-20 Isomer 1: methyl 3-(2-oxo- 13 and 16 a (400MHz, DMSO-d₆) δ: 1.31-1.54 (m, 6 H), 1.55- B m/z 323 (M + H)⁺ (ES+), at1,3,8-triazaspiro[4.5]dec-8- 1.69 (m., 4 H), 1.71-1.90 (m, 2 H),2.09-2.28 (m, 2 1.81 min, UV inactive yl)-8- H), 2.50-2.62 (m, 2 H),2.68-2.83 (m, 1 H), 2.97- azabicyclo[3.2.1]octane-8- 3.04 (m, 2 H),3.52-3.59 (m, 3 H), 4.06-4.16 (m, 2 carboxylate H), 6.05 (s, 1 H), 6.46(br. s., 1 H) 2-20 Isomer 2: ethyl 2-fluoro-3-(2- 13 and16 a (400 MHz,DMSO-d₆) δ: 1.52-1.61 (m, 4 H), 1.69-1.84 B m/z 323 (M + H)⁺ (ES+), atoxo-1-oxa-3,8- (m, 6 H), 1.84-1.93 (m, 2 H), 2.13 (d, J = 13.0 Hz, 21.84 min, UV inactive diazaspiro[4.5]dec-8-yl)-8- H), 2.17-2.25 (m, 2H), 2.59-2.71 (m, 1 H), 3.02 (s, azabicyclo[3.2.1]octane-8- 2 H), 3.55(s, 3 H), 3.94-4.10 (m, 2 H), 6.07 (s, 1 H), carboxylate 6.45 (br. s., 1H) 2-21 Mixture of isomers: ethyl 3- 13 and 17 a (400 MHz, CDCl₃) δ:1.21-1.28 (m, 6 H), 1.74-1.87 B m/z 337 (M + H)⁺ (ES+), at (2-oxo-1,3,8-(m, 2 H), 1.87-2.06 (m, 6 H), 2.46-2.64 (m, 2 H), 2.16 min, UV inactivetriazaspiro[4.5]dec-8-yl)-8- 2.65-2.81 (m, 2 H), 2.87-3.07 (m, 2 H),3.33-3.42 azabicyclo[3.2.1]octane-8- (m, 2 H), 3.45-3.63 (m, 2 H), 4.12(q, J = 7.5 Hz, 2 carboxylate H), 4.34-4.52 (m, 2 H) 2-22 Isomer 1:ethyl 3-(1-benzyl- 17 and 67 b (400 MHz, MeOD-d₄) δ: 1.25-1.34 (m, 6 H),1.54- G m/z 427 (M + H)⁺ (ES⁺), at 3-oxo-1,2,8- 1.65 (m, 2 H), 1.65-1.70(m, 1 H), 1.73-2.02 (m, 10 5.25 min, UV activetriazaspiro[4.5]dec-8-yl)-8- H), 2.40-2.57 (m, 2 H), 2.73-2.86 (m, 2 H),3.86- azabicyclo[3.2.1]octane-8- 3.98 (m, 2 H), 4.15 (q, J = 6.8 Hz, 2H), 4.29-4.35 carboxylate (m, 2 H), 7.18-7.44 (m, 5 H) 2-23 Mixture ofdistereomers: 17 and 82 g (400 MHz, CDCl₃): δ 1.24-1.28 (m, 3H),1.59-2.05 I m/z 429 (M + H)⁺ (ES⁺), at Ethyl 3-(2-oxo-4-(pyridin-2- (m,11 H), 2.51-2.69 (m, 2H), 2.79-2.89 (m, 3H), 3.68 min, UV activeylmethyl)-1-oxa-3,8- 2.94 (d, J = 7.0 Hz, 2 H), 3.94 (t, J = 7.0 Hz,1H), 4.13 diazaspiro[4.5]decan-8-yl)- (q, J = 7.0 Hz, 2H), 4.25-4.41 (m,2H), 6.05 (s, 1H), 8-azabicyclo[3.2.1]octane-8- 7.13-7.19 (m, 2H), 7.63(td, J = 7.5, 2.0 Hz, 1H), 8.50 carboxylate (d, J = 4.0 Hz, 1H) 2-24Ethyl (3-endo)-3-(2-hydroxy- 64 h (400 MHz, DMSO-d₆) δ: 1.14 (t, J = 7.0Hz, 3 H), 1.44- E m/z 352 (M + H)⁺ (ES⁺), at 3-oxo-2,8- 1.64 (m, 4 H),1.75-1.95 (m, 9 H), 2.06 (s, 2 H), 2.14- 1.27 min, UV inactivediazaspiro[4.5]dec-8-yl)-8- 2.24 (m, 1 H), 2.24-2.46 (m, 3 H), 3.22 (s,2 H), azabicyclo[3.2.1]octane-8- 3.94-4.08 (m, 4 H), 9.54 (br. s., 1 H)carboxylate 2-25 Isomer 2: ethyl 3-(3-oxo-2- 73 and i (400 MHz, DMSO-d₆)δ: 0.80 (t, J = 7.5 Hz, 3 H), 1.17 E m/z 378 (M + H)⁺ (ES⁺), atpropyl-2,8- Example (t, J = 7.0 Hz, 3 H), 1.37-1.49 (m, 2 H), 1.49-1.623.67 min, UV inactive diazaspiro[4.5]dec-8-yl)-8- 2-2 (m, 4 H),1.68-1.86 (m, 6 H), 1.86-1.99 (m, 2 H), azabicyclo[3.2.1]octane-8- 2.11(s, 2 H), 2.18-2.28 (m, 1 H), 2.28-2.48 (m, 3 carboxylate H), 2.41-2.66(m, 1H), 3.03-3.19 (m, 4 H), 3.96- 4.12 (m, 4 H) 2-26 Isomer 2: ethyl3-[3-oxo-2- 74 and i (400 MHz, DMSO-d₆) δ: 1.03 (d, J = 6.7 Hz, 6 H),1.17 E m/z 378 (M + H)⁺ (ES⁺), at (propan-2-yl)-2,8- Example (t, J = 7.2Hz, 3 H), 1.45-1.55 (m, 4 H), 1.71-1.86 (m, 3.61 min, UV inactivediazaspiro[4.5]dec-8-yl]-8- 2-2 6 H), 1.86-2.00 (m, 3 H), 2.09 (s, 2 H),2.28-2.32 azabicyclo[3.2.1]octane-8- (m, 1 H), 2.30-2.48 (m, 3 H),2.53-2.59 (m, 1 H), carboxylate 3.05 (s, 2 H), 3.98-4.10 (m, 4 H) 2-27Isomer 2: ethyl 3-[2-(2- 75 and i (400 MHz, DMSO-d₆) δ: 0.81 (d, J = 6.7Hz, 6 H), 1.17 E m/z 392 (M + H)⁺ (ES⁺), at methylpropyl)-3-oxo-2,8-Example (t, J = 7.0 Hz, 3 H), 1.47-1.62 (m, 4 H), 1.72-1.96 4.01 min, UVinactive diazaspiro[4.5]dec-8-yl]-8- 2-2 (m, 8 H), 2.13 (s, 2 H),2.19-2.27 (m, 1 H), 2.29- azabicyclo[3.2.1]octane-8- 2.48 (m, 3 H),2.58-2.64 (m, 2 H), 2.95 (d, J = 7.3 Hz, carboxylate 2 H), 3.11 (s, 2H), 3.96-4.12 (m, 4 H) 2-28 Isomer 2: ethyl 3-[2- 84 and i (400 MHz,DMSO-d₆) δ: 0.08-0.22 (m, 2 H), 0.35- E m/z 390 (M + H)⁺ (ES⁺), at(cyclopropylmethyl)-3-oxo- Example 0.50 (m, 2 H), 0.79-0.94 (m, 1 H),1.17 (t, J = 7.0 Hz, 3 3.78 min, UV inactive2,8-diazaspiro[4.5]dec-8-yl]- 2-2 H), 1.42-1.66 (m, 4 H), 1.71-1.97 (m,8 H), 2.04- 8-azabicyclo[3.2.1]octane-8- 2.16 (m, 2 H), 2.18-2.28 (m, 1H), 2.29-2.46 (m, 2 carboxylate H), 2.53-2.65 (m, 2 H), 3.01 (d, J = 7.0Hz, 2 H), 3.21 (s, 2 H), 3.94-4.14 (m, 4 H) 2-29 Isomer 2: ethyl3-[2-(2- 76 and i (400 MHz, MeOD-d₄) δ: 1.27 (t, J = 7.2 Hz, 3 H), 1.55-E m/z 394 (M + H)⁺ (ES⁺), at methoxyethyl)-3-oxo-2,8- Example 1.76 (m, 6H), 1.88 (d, J = 7.9 Hz, 2 H), 1.95 (br. s., 2 3.13 min, UV inactivediazaspiro[4.5]dec-8-yl]-8- 2-2 H), 2.14-2.32 (m, 4 H), 2.32-2.39 (m, 1H), 2.49- azabicyclo[3.2.1]octane-8- 2.73 (m, 3 H), 3.35 (s, 3 H),3.42-3.49 (m, 2 H), 3.49- carboxylate 3.56 (m, 2 H), 3.56-3.73 (m, 3 H),4.06-4.21 (m, 2 H), 4.22-4.36 (m, 2 H) 2-30 Isomer 1: (1,1-²H₂)ethyl 3-58 and 60 j (400 MHz, DMSO-d₆) δ: 1.13 (s, 3 H), 1.34-1.54 (m, 6 E m/z338 (M + H)⁺ (ES⁺), at (3-oxo-2,8- H), 1.54-1.71 (m, 4 H), 1.71-1.91 (m,2 H), 1.94 (s, 1.76 min, UV inactive diazaspiro[4.5]dec-8-yl)-8- 2 H),2.32-2.42 (m, 3 H), 2.51-2.59 (m, 1 H), 2.67- azabicyclo[3.2.1]octane-8-2.79 (m, 1 H), 2.95 (s, 2 H), 4.02-4.19 (m, 2 H), 7.46 carboxylate (s, 1H) 2-30 Isomer 2: (1,1-²H₂)ethyl 3- 58 and 60 j (400 MHz, DMSO-d₆) δ:1.13 (s, 3 H), 1.52 (t, J = 5.7 E m/z 338 (M + H)⁺ (ES⁺), at (3-oxo-2,8-Hz, 5 H), 1.68-1.93 (m, 9 H), 1.96 (s, 2 H), 2.14- 1.80 min, UV inactivediazaspiro[4.5]dec-8-yl)-8- 2.29 (m, 1 H), 2.34-2.44 (m, 1 H), 2.52-2.61(m, 1 azabicyclo[3.2.1]octane-8- H), 2.97 (s, 2 H), 4.03 (dt, J = 7.1,3.7 Hz, 2 H), 7.47 carboxylate (s, 1 H) 2-31 Isomer 1: (2,2,2-²H₃)ethyl3- 58 and 61 j (400 MHz, DMSO-d₆) δ: 1.33-1.54 (m, 6 H), 1.54- E m/z 339(M + H)⁺ (ES⁺), at (3-oxo-2,8- 1.72 (m, 4 H), 1.72-1.89 (m, 2 H), 1.94(s, 2 H), 2.32- 1.76 min, UV inactive diazaspiro[4.5]dec-8-yl)-8- 2.44(m, 3 H), 2.51-2.62 (m, 1 H), 2.67-2.84 (m, azabicyclo[3.2.1]octane-8- 1H), 2.95 (s, 2 H), 4.00 (s, 2 H), 4.04-4.20 (m, 2 H), carboxylate 7.46(s, 1 H) 2-31 Isomer 2: (2,2,2-²H₃)ethyl 3- 58 and 61 j (400 MHz,DMSO-d₆) δ: 1.52 (t, J = 5.5 Hz, 5 H), 1.69- E m/z 339 (M + H)⁺ (ES⁺),at (3-oxo-2,8- 1.92 (m, 9 H), 1.96 (s, 2 H), 2.13-2.24 (m, 1 H), 1.83min, UV inactive diazaspiro[4.5]dec-8-yl)-8- 2.35-2.44 (m, 1 H),2.52-2.58 (m, 1 H), 2.97 (s, 2 azabicyclo[3.2.1]octane-8- H), 3.96-4.07(m, 4 H), 7.47 (s, 1 H) carboxylate 2-32 Isomer 1: (²H₅)ethyl 3-(3- 58and 59 j (400 MHz, DMSO-d₆) δ: 1.34-1.55 (m, 6 H), 1.56- E m/z 341 (M +H)⁺ (ES⁺), at oxo-2,8-diazaspiro[4.5]dec- 1.72 (m, 4 H), 1.75-1.89 (m, 2H), 1.95 (s, 2 H), 2.33- 1.76 min, UV inactive 8-yl)-8- 2.42 (m, 2 H),2.52-2.60 (m, 2 H), 2.68-2.86 (m, azabicyclo[3.2.1]octane-8- 1 H), 2.95(s, 2 H), 4.03-4.20 (m, 2 H), 7.47 (s, 1 H) carboxylate 2-32 Isomer 2:(²H₅)ethyl 3-(3- 58 and 59 j (400 MHz, DMSO-d₆) δ: 1.52 (t, J = 5.5 Hz,5 H), 1.60- E m/z 341 (M + H)⁺ (ES⁺), at oxo-2,8-diazaspiro[4.5]dec-1.92 (m, 9 H), 1.96 (s, 2 H), 2.14-2.27 (m, 1 H), 1.88 min, UV inactive8-yl)-8- 2.35-2.45 (m, 1 H), 2.56-2.61 (m, 1 H), 2.97 (s, 2azabicyclo[3.2.1]octane-8- H), 3.96-4.08 (m, 2 H), 7.48 (s, 1 H)carboxylate 2-33 Isomer 1: propan-2-yl 3-(3- 1 and 68 b (400 MHz,DMSO-d₆) δ: 1.14-1.23 (m, 6 H), 1.37- E m/z 350 (M + H)⁺ (ES⁺), atoxo-2,8-diazaspiro[4.5]dec- 1.57 (m, 6 H), 1.57-1.74 (m, 4 H), 1.74-1.93(m, 2 2.97 min, UV inactive 8-yl)-8- H), 1.97 (s, 2 H), 2.36 (d, J =18.9 Hz, 4 H), 2.76 (dt, J = azabicyclo[3.2.1]octane-8- 11.0, 5.8 Hz, 1H), 2.98 (s, 2 H), 4.07-4.17 (m, 2 carboxylate H), 4.78 (dt, J = 12.4,6.1 Hz, 1 H), 7.49 (s, 1 H) 2-33 Isomer 2: propan-2-yl 3-(3- 1 and 68 b(400 MHz, DMSO-d₆) δ: 1.10-1.26 (m, 7 H), 1.44- E m/z 350 (M + H)⁺(ES⁺), at oxo-2,8-diazaspiro[4.5]dec- 2.12 (m, 15 H), 2.15-2.46 (m 3 H),2.98-3.03 (m, 2 3.03 min, UV inactive 8-yl)-8- H), 3.95-4.20 (m, 2 H),4.73-4.84 (m, 1 H), 7.54 (br. azabicyclo[3.2.1]octane-8- s., 1 H)carboxylate 2-34 Isomer 1: S-methyl 3-(3- 1 and 71 b (400 MHz, DMSO-d₆)δ: 1.44-1.53 (m, 6 H), 1.61- E m/z 338 (M + H)⁺ (ES⁺), atoxo-2,8-diazaspiro[4.5]dec- 1.93 (m, 6 H), 1.97 (s, 2 H), 2.25 (s, 3 H),2.28-2.46 2.53 min, UV inactive 8-yl)-8- (m, 5 H), 2.73-2.89 (m, 1 H),2.98 (s, 2 H), 4.09- azabicyclo[3.2.1]octane-8- 4.50 (m, 1H), 7.50 (br.s., 1 H) carbothioate 2-34 Isomer 2: S-methyl 3-(3- 1 and 71 b (400 MHz,DMSO-d₆) δ: 1.43-1.63 (m, 4 H), 1.74- E m/z 338 (M + H)⁺ (ES⁺), atoxo-2,8-diazaspiro[4.5]dec- 2.04 (m, 10 H), 2.17-2.37 (m, 6 H),2.37-2.49 (m, 2 2.63 min, UV inactive 8-yl)-8- H), 2.54-2.62 (m, 1 H),3.00 (s, 2 H), 3.99-4.48 (m, azabicyclo[3.2.1]octane-8- 1 H), 7.51 (br.s., 1 H) carbothioate 2-35 Isomer 1: S-ethyl 3-(3-oxo- 1 and 77 b (400MHz, DMSO-d₆) δ: 1.19 (t, J = 7.3 Hz, 3 H), 1.39- E m/z 352 (M + H)⁺(ES⁺), at 2,8-diazaspiro[4.5]dec-8-yl)- 1.58 (m, 6 H), 1.58-1.78 (m, 4H), 1.78-1.94 (m, 2 2.87 min, UV inactive 8-azabicyclo[3.2.1]octane-8-H), 1.94-2.03 (m, 2 H), 2.36 (d, J = 19.8 Hz, 4 H), carbothioate2.72-2.86 (m, 3 H), 2.97 (s, 2 H), 4.09-4.17 (m, 1 H), 4.33-4.58 (m, 1H), 7.50 (s, 1 H) 2-35 Isomer 2: S-ethyl 3-(3-oxo- 1 and 77 b (400 MHz,MeOD-d₄) δ: 1.26-1.32 (m, 3 H), 1.59- E m/z 352 (M + H)⁺ (ES⁺), at2,8-diazaspiro[4.5]dec-8-yl)- 1.75 (m, 6 H), 1.75-1.88 (m, 2 H),1.88-2.10 (m, 4 2.96 min, UV inactive 8-azabicyclo[3.2.1]octane-8- H),2.23 (s, 2 H), 2.45-2.56 (m, 2 H), 2.56-2.72 (m, carbothioate 2 H),2.79-2.97 (m, 3 H), 3.20 (s, 2 H), 4.22-4.42 (m, 1 H), 4.59-4.73 (m, 2H) 3-1 Isomer 1: ethyl 5-(3-oxo-2,8- 1 and 25 k (300 MHz, DMSO-d₆) δ:1.15-1.28 (m, 3 H), 1.44- E m/z 336 (M + H)⁺ (ES⁺), atdiazaspiro[4.5]dec-8-yl)-2- 1.67 (m, 7 H), 1.71 (d, J = 10.1 Hz, 2 H),1.85-2.02 2.81 min, UV inactive azabicyclo[2.2.2]octane-2- (m, 1 H),2.06 (s, 2 H), 2.11-2.25 (m, 2 H), 2.25- carboxylate 2.53 (m, 4 H), 3.06(s, 2 H), 3.09-3.25 (m, 1 H), 3.43- 3.52 (m, 1 H), 3.95 (d, J = 8.2 Hz,1 H), 4.06 (q, J = 7.1 Hz, 2 H), 7.52 (br. s., 1 H) 3-1 Isomer 2: ethyl5-(3-oxo-2,8- 1 and 25 k (400 MHz, CDCl₃) δ: 1.21-1.30 (m, 3 H),1.38-1.49 E m/z 336 (M + H)⁺ (ES⁺), at diazaspiro[4.5]dec-8-yl)-2- (m, 2H), 1.62-1.95 (m, 9 H), 2.05-2.20 (m, 3 H), 2.64 min, UV inactiveazabicyclo[2.2.2]octane-2- 2.21 (s, 2 H), 2.26-2.66 (m, 2 H), 3.19 (s, 2H), 3.25- carboxylate 3.35 (m, 1 H), 3.35-3.48 (m, 1 H), 3.92-4.09 (m, 1H), 4.13 (q, J = 7.2 Hz, 2 H), 5.69 (br. s., 1 H) 3-1 Isomer 3: ethyl5-(3-oxo-2,8- 1 and 25 k (400 MHz, CDCl₃) δ: 1.18-1.31 (m, 3 H),1.40-1.62 E m/z 336 (M + H)⁺ (ES⁺), at diazaspiro[4.5]dec-8-yl)-2- (m, 2H), 1.62-1.76 (m, 8 H), 1.77-1.98 (m, 2 H), 2.80 min, UV inactiveazabicyclo[2.2.2]octane-2- 2.09-2.19 (m, 2 H), 2.20 (d, J = 2.3 Hz, 2H), 2.25- carboxylate 2.69 (m, 2 H), 3.18 (d, J = 3.8 Hz, 2 H),3.20-3.28 (m, 1 H), 3.55 (d, J = 11.0 Hz, 1 H), 3.96-4.20 (m, 3 H), 5.64(br. s., 1 H) 3-1 Isomer 4: ethyl 5-(3-oxo-2,8- 1 and 25 k (400 MHz,CDCl₃) δ: 1.20-1.30 (m, 3 H), 1.37-1.51 E m/z 336 (M + H)⁺ (ES⁺), atdiazaspiro[4.5]dec-8-yl)-2- (m, 2 H), 1.64-1.98 (m, 9 H), 1.99-2.20 (m,3 H), 2.64 min, UV inactive azabicyclo[2.2.2]octane-2- 2.21 (s, 2 H),2.33-2.66 (m, 2 H), 3.19 (s, 2 H), 3.24- carboxylate 3.36 (m, 1 H),3.36-3.47 (m, 1 H), 3.91-4.09 (m, 1 H), 4.13 (q, J = 7.0 Hz, 2 H), 5.69(br. s., 1 H) 3-2 Isomer 1 (racemic): ethyl 5- 8 and 25 c (300 MHz,MeOD-d₄) δ: 1.16-1.32 (m, 3H), 1.40- C m/z 338 (M + H)⁺ (ES+), at(2-oxo-1-oxa-3,8- 1.57 (m, 2H), 1.65-2.03 (m, 7H), 2.03-2.24 (m, 1.37min, UV inactive diazaspiro[4.5]dec-8-yl)-2- 2H), 2.24-2.37 (m, 1H),2.38-2.85 (m, 4H), 3.24- azabicyclo[2.2.2]octane-2- 3.50 (m, 4H),3.94-4.02 (m, 1H), 4.10 (q, J = 7.0 Hz, carboxylate 2H), NH not observed3-2 Isomer 2 (racemic): ethyl 5- 8 and 25 c (300 MHz, MeOD-d₄) δ:1.18-1.31 (m, 3H), 1.51- C m/z 338 (M + H)⁺ (ES+), at (2-oxo-1-oxa-3,8-2.09 (m, 10H), 2.17-2.34 (m, 2H), 2.34-2.57 (m, 1.41 min, UV inactivediazaspiro[4.5]dec-8-yl)-2- 2H), 2.58-2.81 (m, 2H), 3.16-3.39 (m, 3H),3.48- azabicyclo[2.2.2]octane-2- 3.63 (m, 1H), 3.98-4.05 (m, 1H), 4.11(q, J = 7.0 Hz, carboxylate 2H), NH not observed 3-3 Isomer 2 (racemic):ethyl 5- 10 and 25 l (300 MHz, CDCl₃) δ: 0.91 (t, J = 7.4 Hz, 3H), 1.08-E m/z 366 (M + H)⁺ (ES+), at (4-ethyl-2-oxo-1-oxa-3,8- 1.27 (m, 3H),1.29-1.96 (m, 11H), 2.02-2.36 (m, 3.27 min, UV activediazaspiro[4.5]dec-8-yl)-2- 4H), 2.71-2.97 (m, 2H), 3.09-3.32 (m, 2H),3.43- azabicyclo[2.2.2]octane-2- 3.58 (m, 1H), 3.88-4.15 (m, 3H),5.90-6.18 (m, 1H) carboxylate 3-4 Isomer 1 (racemic): ethyl 5- 25 and 86l (300 MHz, CDCl₃) δ: 1.09-1.28 (m, 4H), 1.28-1.47 E m/z 420 (M + H)⁺(ES+), at [2-oxo-4-(2,2,2- (m, 2H), 1.47-2.39 (m, 13H), 2.75-2.96 (m,2H), 3.41 min, UV active trifluoroethyl)-1-oxa-3,8- 3.17-3.46 (m, 2H),3.70 (d, J = 9.5 Hz, 1H), 3.84- diazaspiro[4.5]dec-8-yl]-2- 4.17 (m,3H), 5.54 (br. s., 1H) azabicyclo[2.2.2]octane-2- carboxylate 3-4 Isomer2 (racemic): ethyl 5- 25 and 86 l (300 MHz, CDCl₃) δ: 0.80-1.04 (m, 4H),1.10-1.35 E m/z 420 (M + H)⁺ (ES+), at [2-oxo-4-(2,2,2- (m, 7H),1.35-1.98 (m, 6H), 1.98-2.83 (m, 9H), 3.12- 3.49 min, UV activetrifluoroethyl)-1-oxa-3,8- 3.38 (m, 2H), 3.54 (d, J = 10.5 Hz, 1H),3.92-4.23 diazaspiro[4.5]dec-8-yl]-2- (m, 4H), 7.36 (s, 1H).azabicyclo[2.2.2]octane-2- carboxylate 3-5 Isomer 1 (racemic): ethyl 5-25 and 88 l (400 MHz, CDCl₃) δ: 0.73-0.99 (m, 3H), 0.99-1.55 E m/z 379(M + H)⁺ (ES+), at (3-oxo-1-propyl-1,2,8- (m, 11H), 1.56-3.05 (m, 13H),3.11-3.75 (m, 2H), 3.16 min, UV active triazaspiro[4.5]dec-8-yl)-2-3.85-4.28 (m, 4H), 7.34 (br. s., 1H) azabicyclo[2.2.2]octane-2-carboxylate 3-5 Isomer 2 (racemic): ethyl 5- 25 and 88 l (400 MHz,CDCl₃) δ: 0.80-1.04 (m, 4H), 1.10-1.35 E m/z 379 (M + H)⁺ (ES+), at(3-oxo-1-propyl-1,2,8- (m, 7H), 1.35-1.98 (m, 6H), 1.98-2.83 (m, 9H),3.12- 3.25 min, UV active triazaspiro[4.5]dec-8-yl)-2- 3.38 (m, 2H),3.54 (d, J = 10.5 Hz, 1H), 3.92-4.23 azabicyclo[2.2.2]octane-2- (m, 4H),7.36 (s, 1H). carboxylate 4-1 Isomer 2: ethyl 8-(3-oxo-2,8- 1 and 27 a(300 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.0 Hz, 3 H), 1.35- E m/z 336 (M +H)⁺ (ES+), at diazaspiro[4.5]dec-8-yl)-3- 1.49 (m, 2 H), 1.56 (t, J =5.0 Hz, 4 H), 1.61-1.75 3.11 min, UV inactive azabicyclo[3.2.1]octane-3-(m, 2 H), 2.01 (s, 2 H), 2.05-2.13 (m, 1 H), 2.13- carboxylate 2.42 (m,6 H), 3.01 (s, 2 H), 3.05-3.26 (m, 2 H), 3.36- 3.49 (m, 2 H), 4.00 (q, J= 7.0 Hz, 2 H), 7.48 (br. s., 1 H) 5-1 Isomer 1: ethyl 3-(3-oxo-2,8- 1and 28 e (400 MHz, CDCl₃) δ: 1.15-2.08 (m, 16 H), 2.11-2.87 D m/z 350(M + H)⁺ (ES+), at diazaspiro[4.5]dec-8-yl)-9- (m, 8 H), 3.18 (s, 2 H),4.03-4.24 (m, 2 H), 4.35- 2.75 min, UV inactiveazabicyclo[3.3.1]nonane-9- 4.66 (m, 2 H), 5.78 (br. s., 1 H) carboxylate5-1 Isomer 2: ethyl 3-(3-oxo-2,8- 1 and 28 e (400 MHz, CDCl₃) δ: 1.25(t, J = 7.0 Hz, 3 H), 1.51- D m/z 350 (M + H)⁺ (ES+), atdiazaspiro[4.5]dec-8-yl)-9- 2.01 (m, 14 H), 2.20 (s, 2 H), 2.30-2.80 (m,4 H), 2.7 min, UV inactive azabicyclo[3.3.1]nonane-9- 3.04-3.34 (m, 3H), 4.12 (q, J = 7.0 Hz, 2 H), 4.29- carboxylate 4.54 (m, 2 H), 5.87(br. s., 1 H) 5-2 Isomer 1: prop-2-yn-1-yl 3- 1 and 30 d (400 MHz,CDCl₃) δ: 1.24-1.49 (m, 5 H), 1.49-1.74 D m/z 360 (M + H)⁺ (ES+), at(3-oxo-2,8- (m, 7 H), 1.80-1.98 (m, 1 H), 2.13-2.37 (m, 5 H), 2.08 min,UV inactive diazaspiro[4.5]dec-8-yl)-9- 2.41-2.66 (m, 4 H), 3.16 (s, 2H), 4.40-4.57 (m, 2 azabicyclo[3.3.1]nonane-9- H), 4.68 (s, 2 H), 5.80(br. s., 1 H) carboxylate 5-2 Isomer 2: prop-2-yn-1-yl 3- 1 and 30 d(400 MHz, CDCl₃) δ: 1.54-1.92 (m, 14 H), 2.18 (s, 2 D m/z 360 (M + H)⁺(ES+), at (3-oxo-2,8- H), 2.34-2.51 (m, 3 H), 2.51-2.66 (m, 2 H), 3.10-2.10 min, UV inactive diazaspiro[4.5]dec-8-yl)-9- 3.24 (m, 3 H),4.33-4.47 (m, 2 H), 4.63-4.73 (m, 2 azabicyclo[3.3.1]nonane-9- H), 5.88(s, 1 H) carboxylate 5-3 Mixture of isomers: but-2- 1 and 31 d (400 MHz,CDCl₃) δ: 1.11-1.96 (m, 16 H), 2.06-2.72 D m/z 374 (M + H)⁺ (ES+), atyn-1-yl 3-(3-oxo-2,8- (m, 7 H), 3.15 (s, 3 H), 4.26-4.71 (m, 4 H), 6.29(s, 1 H) 2.26 min, UV inactive diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9- carboxylate 5-4 Isomer 1: ethyl 3-(2-oxo-1- 8and 28 e (400 MHz, CDCl₃) δ: 0.97-2.14 (m, 16 H), 2.14-3.08 D m/z 352(M + H)⁺ (ES+), at oxa-3,8-diazaspiro[4.5]dec- (m, 6 H), 3.21-3.53 (m, 2H), 3.97-4.22 (m, 2 H), 2.15 min, UV inactive 8-yl)-9- 4.33-4.68 (m, 2H), 5.07 (br. s., 1 H) azabicyclo[3.3.1]nonane-9- carboxylate 5-4 Isomer2: ethyl 3-(2-oxo-1- 8 and 28 e (400 MHz, CDCl₃) δ: 0.70-2.41 (m, 19 H),2.64-2.92 D m/z 352 (M + H)⁺ (ES+), at oxa-3,8-diazaspiro[4.5]dec- (m, 3H), 3.35 (s, 2 H), 3.99-4.19 (m, 2 H), 4.29- 2.23 min, UV inactive8-yl)-9- 4.50 (m, 2 H), 5.13 (br. s., 1 H) azabicyclo[3.3.1]nonane-9-carboxylate 6-1 Isomer 1: methyl 3-(3-oxo- 1 and 33 a (400 MHz, DMSO-d₆)δ: 1.23-1.37 (m, 1 H), 1.37- E m/z 322 (M + H)⁺ (ES+), at2,8-diazaspiro[4.5]dec-8-yl)- 1.57 (m, 5 H), 1.64-1.82 (m, 2 H),1.88-2.04 (m, 1 1.99 min, UV inactive 6-azabicyclo[3.2.1]octane-6- H),1.98 (s, 2 H), 2.30-2.48 (m, 5 H), 2.99 (s, 2 H), carboxylate 3.08-3.20(m, 2 H), 3.22-3.33 (m, 2 H), 3.58 (s, 3 H), 3.99-4.07 (m, 1 H), 7.51(br s, 1 H). 6-1 Isomer 2: methyl 3-(3-oxo- 1 and 33 a (400 MHz,DMSO-d₆) δ: 1.44-1.55 (m, 3 H), 1.56- E m/z 322 (M + H)⁺ (ES+), at2,8-diazaspiro[4.5]dec-8-yl)- 1.76 (m, 5 H), 1.82-1.93 (m, 1 H), 1.98(s, 2 H), 2.30- 2.12 min, UV inactive 6-azabicyclo[3.2.1]octane-6- 2.46(m, 5 H), 2.99 (s, 2 H), 3.08-3.36 (m, 4 H), carboxylate 3.58 (s, 3 H),3.87-3.95 (m, 1 H), 7.51 (br s, 1 H). 6-2 Isomer 2: ethyl 3-(3-oxo-2,8-1 and 34 a (400 MHz, DMSO-d₆) δ: 1.06-1.27 (m, 3 H), 1.35- E m/z 336(M + H)⁺ (ES+), at diazaspiro[4.5]dec-8-yl)-6- 1.75 (m, 7 H), 1.77-1.88(m, 1 H), 1.88-2.04 (m, 3 2.37 min, UV inactiveazabicyclo[3.2.1]octane-6- H), 2.09-2.70 (m, 6 H), 2.94 (s, 2 H),3.04-3.19 (m, carboxylate 1 H), 3.25-3.39 (m, 2 H), 3.82-4.11 (m, 3 H),7.46 (s, 1 H) 6-3 Isomer 1: ethyl 3-(2-oxo-1- 8 and 34 a (400 MHz,DMSO-d₆) δ: 1.07-1.21 (m, 3 H) 1.21- E m/z 338 (M + H)⁺ (ES+), atoxa-3,8-diazaspiro[4.5]dec- 1.53 (m, 2 H), 1.57-1.83 (m, 6 H), 1.86-2.01(m, 1 2.34 min, UV inactive 8-yl)-6- H), 2.25-2.55 (m, 6 H), 3.02-3.43(m, 5 H), 3.87- azabicyclo[3.2.1]octane-6- 4.10 (m, 3 H), 7.43 (s, 1 H)carboxylate 6-3 Isomer 2: ethyl 3-(2-oxo-1- 8 and 34 a (400 MHz,DMSO-d₆) δ: 1.05-1.32 (m, 4 H) 1.50- E m/z 338 (M + H)⁺ (ES+), atoxa-3,8-diazaspiro[4.5]dec- 2.06 (m, 8 H), 2.21-2.70 (m, 6 H), 3.02-3.48(m, 5 2.50 min, UV inactive 8-yl)-6- H), 3.81-4.10 (m, 3 H), 7.43 (br.s., 1 H) azabicyclo[3.2.1]octane-6- carboxylate 7-1 Isomer 1: ethyl6-(2-oxo-1- 8 and 35 f (400 MHz, DMSO-d₆) δ: 1.07-1.27 (m, 5 H), 1.57- Em/z 338 (M + H)⁺ (ES+), at oxa-3,8-diazaspiro[4.5]dec- 1.82 (m, 4H),1.96-2.12 (m, 2 H), 2.33-2.45 (m, 3 2.52 min, UV inactive 8-yl)-3- H),2.52-2.61 (m, 2 H), 3.07-3.22 (m, 4 H), 3.35- azabicyclo[3.2.1]octane-3-3.41 (m, 4 H), 3.98 (q, J = 7.0 Hz, 2 H), 7.44 (s, 1 H) carboxylate 8-1Isomer 1: ethyl 6-(3-oxo-2,8- 1 and 63 m (400 MHz, CDCl₃) δ: 1.26 (t, J= 7.2 Hz, 3 H), 1.31- E m/z 322 (M + H)⁺ (ES⁺), atdiazaspiro[4.5]dec-8-yl)-3- 1.47 (m, 1 H), 1.55-1.90 (m, 4 H), 2.21 (s,3 H), 2.27- 2.43 min, UV inactive azabicyclo[3.1.1]heptane-3- 2.70 (m, 7H), 3.19 (s, 2 H), 3.50 (d, J = 10.9 Hz, 2 carboxylate H), 3.71 (t, J =10.9 Hz, 2 H), 4.15 (q, J = 7.0 Hz, 2 H), 5.89 (br. s., 1 H) 9-1 Isomer1: ethyl 3-(3-oxo-2,8- 17 and 66 n (400 MHz, DMSO-d₆) δ: 1.15 (t, J =7.0 Hz, 3 H), 1.37- E m/z 350 (M + H)⁺ (ES⁺), atdiazaspiro[4.6]undec-8-yl)- 1.74 (m, 13 H), 1.73-1.89 (m, 2 H), 1.97 (s,2 H), 2.84 min, UV inactive 8-azabicyclo[3.2.1]octane-8- 2.32-2.48 (m,1H), 2.52-2.60 (m, 2 H), 2.96 (s, 2 H), carboxylate 2.98-3.11 (m, 1 H),3.92-4.07 (m, 2 H), 4.12 (br. s., 2 H), 7.43 (s, 1 H) 9-1 Isomer 2:ethyl 3-(3-oxo-2,8- 17 and 66 n (400 MHz, DMSO-d₆) δ: 1.14 (t, J = 7.0Hz, 3 H), 1.45- E m/z 350 (M + H)⁺ (ES⁺), at diazaspiro[4.6]undec-8-yl)-1.66 (m, 9 H), 1.71-1.85 (m, 4 H), 1.86-1.96 (m, 2 2.81 min, UV inactive8-azabicyclo[3.2.1]octane-8- H), 1.98 (d, J = 2.7 Hz, 2 H), 2.40-2.45(m, 1 H), 2.52- carboxylate 2.60 (m, 3 H), 2.97 (s, 2 H), 3.93-4.03 (m,2 H), 4.03-4.11 (m, 2 H), 7.43 (s, 1 H) 9-2 Isomer 1: ethyl 3-(2-oxo-1-17 and 80 o ¹H NMR (400 MHz, DMSO-d₆) δ: 1.17 (t, J = 7.0 Hz, 3 E m/z352 (M + H)⁺ (ES⁺), at oxa-3,8- H), 1.34-1.54 (m, 3 H), 1.54-1.72 (m, 5H), 1.72- 2.96 min, UV inactive diazaspiro[4.6]undec-8-yl)- 1.92 (m, 6H), 2.39-2.47 (m, 1 H), 2.54-2.57 (m, 8-azabicyclo[3.2.1]octane-8- 1H),2.60 (t, J = 5.8 Hz, 2 H), 2.93-3.08 (m, 1 H), carboxylate 3.20 (s, 2H), 3.95-4.10 (m, 2 H), 4.10-4.16 (m, 2 H), 7.41 (s, 1 H) 9-2 Isomer 2:ethyl 3-(2-oxo-1- 17 and 80 o ¹H NMR (400 MHz, DMSO-d₆) δ: 1.17 (t, J =7.0 Hz, 3 E m/z 352 (M + H)⁺ (ES⁺), at oxa-3,8- H), 1.36-1.54 (m, 3 H),1.57-1.72 (m, 5 H), 1.72- 2.96 min, UV inactivediazaspiro[4.6]undec-8-yl)- 1.93 (m, 6 H), 2.38-2.46 (m, 1 H), 2.53-2.57(m, 1 8-azabicyclo[3.2.1]octane-8- H), 2.57-2.64 (m, 2 H), 2.94-3.07 (m,1 H), 3.20 (s, carboxylate 2 H), 4.04 (t, J = 7.2 Hz, 2 H), 4.09-4.19(m, 2 H), 7.40 (s, 1 H) 9-2 Isomer 3: ethyl 3-(2-oxo-1- 17 and 80 o ¹HNMR (400 MHz, DMSO-d₆) δ: 1.17 (t, J = 7.0 Hz, 3 E m/z 352 (M + H)⁺(ES⁺), at oxa-3,8- H), 1.46-1.64 (m, 3 H), 1.67-1.79 (m, 2 H), 1.79-3.03 min, UV inactive diazaspiro[4.6]undec-8-yl)- 2.04 (m, 9 H),2.42-2.48 (m, 2 H), 2.64-2.75 (m, 3 8-azabicyclo[3.2.1]octane-8- H),3.22 (s, 2 H), 3.97-4.06 (m, 2 H), 4.07-4.15 (m, carboxylate 2 H), 7.43(s, 1 H) 9-2 Isomer 4: ethyl 3-(2-oxo-1- 17 and 80 o ¹H NMR (400 MHz,DMSO-d₆) δ: 1.17 (t, J = 7.0 Hz, 3 E m/z 352 (M + H)⁺ (ES⁺), at oxa-3,8-H), 1.49-1.66 (m, 3 H), 1.66-1.88 (m, 9 H), 1.88- 3.04 min, UV inactivediazaspiro[4.6]undec-8-yl)- 2.00 (m, 2 H), 2.42-2.47 (m, 1 H), 2.55-2.67(m, 8-azabicyclo[3.2.1]octane-8- 2H), 2.68-2.75 (m, 2 H), 3.22 (s, 2 H),3.98-4.08 (m, carboxylate 2 H), 4.09-4.16 (m, 2 H), 7.43 (s, 1 H)

Biological Activity Example A Phospho-ERK1/2 Assays

Functional assays were performed using the Alphascreen Surefirephospho-ERK1/2 assay (Crouch & Osmond, Comb. Chem. High ThroughputScreen, 2008). ERK1/2 phosphorylation is a downstream consequence ofboth Gq/11 and Gi/o protein coupled receptor activation, making ithighly suitable for the assessment of M₁, M₃ (Gq/11 coupled) and M₂, M₄receptors (Gi/o coupled), rather than using different assay formats fordifferent receptor subtypes. CHO cells stably expressing the humanmuscarinic M₁, M₂, M₃ or M₄ receptor were plated (25K/well) onto 96-welltissue culture plates in MEM-alpha+10% dialysed FBS. Once adhered, cellswere serum-starved overnight. Agonist stimulation was performed by theaddition of 5 μL agonist to the cells for 5 min (37° C.). Media wasremoved and 50 μL of lysis buffer added. After 15 min, a 4 μL sample wastransferred to 384-well plate and 7 μL of detection mixture added.Plates were incubated for 2 h with gentle agitation in the dark and thenread on a PHERAstar plate reader.

pEC₅₀ and E_(max) figures were calculated from the resulting data foreach receptor subtype.

For most examples two diastereomers exist which have been separated,unless stated otherwise, Analytical data for active isomers is reportedin Table 3. In examples 3-1 and 9-2 the four enantiomers have beenseparated, data is provided for all isomers.

The results are set out in Table 4 below.

TABLE 4 Muscarinic Activity pEC₅₀ M₁ pEC₅₀ M₂ pEC₅₀ M₃ pEC₅₀ M₄ Ex. No.(% Emax cf. ACh) (% Emax cf. ACh) (% Emax cf. ACh) (% Emax cf. ACh) ACh8.3 (102) 7.8 (105) 8.1 (115) 8.1 (110) 2-1 Isomer 2 6.2 (72) NT NT 5.8(25) 2-2 Isomer 1 7.1 (99) <4.7 (0) <4.7 (17) 6.7 (53) 2-2 Isomer 2 7.9(86) <4.7 (0) <4.7 (0) 7.6 (31) 2-3 Isomer 1 6.4 (85) NT NT 5.7 (47) 2-3Isomer 2 7.1 (49) <4.7 (4) <4.7 (0) <4.7 (16) 2-4 Isomer 1 7.0 (92) <4.7(27) <4.7 (7) 6.9 (64) 2-4 Isomer 2 7.7 (86) <4.7 (8) <4.7 (0) 7.6 (53)2-5 Isomer 1 7.6 (98) 6.8 (39) <4.7 (7) 7.6 (87) 2-6 Isomer 2 6.3 (35)NT NT 4.8 (32) 2-8 Isomer 1 7.7 (52) <4.7 (4) 4.9 (50) <4.7 (23) 2-8Isomer 2 7.0 (89) <4.7 (6) <4.7 (12) 7.5 (59) 2-9 Isomer 1 8.3 (91) <4.7(2) <4.7 (22) 8.6 (78) 2-10 Isomer 1 7.7 (74) <4.7 (1) <4.7 (5) 7.1 (21)2-10 Isomer 2 7.2 (77) <4.7 (11) <4.7 (13) 6.9 (50) 2-11 Isomer 1 6.2(95) NT NT 6.0 (53) 2-11 Isomer 2 6.6 (101) <4.7 (18) <4.7 (22) 6.7 (55)2-13 Isomer 2 6.8 (76) <4.7 (11) <4.7 (57) 7.0 (49) 2-14 Isomer 1 6.7(108) NT NT 6.3 (55) 2-14 Isomer 2 7.4 (92) <4.7 (0) <4.7 (0) 7.1 (60)2-15 Isomer 1 7.0 (101) NT NT <4.7 (10) 2-16 Isomer 1 7.3 (36) <4.7 (3)<4.7 (9) 7.1 (19) 2-16 Isomer 2 6.2 (68) NT NT 6.7 (51) 2-17 Isomer 17.5 (58) <4.7 (2) <4.7 (51) 7.7 (25) 2-17 Isomer 2 6.7 (117) <4.7 (3)<4.7 (12) 7.0 (72) 2-18 Isomer 1 6.6 (55) NT NT <4.7 (11) 2-19 Isomer 26.0 (94) NT NT 5.4 (74) Mixture of 6.3 (86) NT NT <4.7 (12) distereomers2-23 2-24 7.2 (88) <4.7 (4) <4.7 (4) <4.7 (29) 2-25 Isomer 2 6.6 (53)<4.7 (15) <4.7 (12) 6.6 (25) 2-26 Isomer 2 6.2 (43) NT NT 6.2 (22) 2-27Isomer 2 6.4 (38) NT NT <4.7 (14) 2-28 Isomer 2 6.3 (57) NT NT 6.5 (27)2-30 Isomer 1 6.9 (107) NT NT 6.7 (49) 2-30 Isomer 2 7.5 (66) <4.7 (9)<4.7 (16) 7.1 (29) 2-31 Isomer 1 6.9 (112) NT NT 6.6 (53) 2-31 Isomer 27.6 (76) <4.7 (11) <4.7 (8) 7.6 (26) 2-32 Isomer 1 7.1 (92) <4.7 (16)<4.7 (10) 6.9 (40) 2-32 Isomer 2 7.5 (77) <4.7 (15) <4.7 (1) 7.3 (48)2-33 Isomer 1 7.5 (37) NT NT 6.7 (20) 2-33 Isomer 2 6.4 (62) NT NT 6.5(25) 2-34 Isomer 1 6.3 (50) NT NT <4.7 (8) 2-35 Isomer 1 7.4 (24) NT NT<4.7 (7) 2-35 Isomer 2 6.1 (50) NT NT <4.7 (10) 3-1 Isomer 1 8.9 (111)8.0 (63) <4.7 (6) 8.4 (61) 3-1 Isomer 2 7.2 (94) <4.7 (11) <4.7 (1) 6.6(31) 3-1 Isomer 3 7.4 (101) <4.7 (17) <4.7 (16) 6.8 (41) 3-1 Isomer 45.9 (62) NT NT <4.7 (7) 3-2 Isomer 1 6.6 (111) NT NT 5.9 (29) 3-2 Isomer2 7.0 (127) NT NT 6.4 (36) 3-3 Isomer 2 6.1 (76) NT NT 6.5 (56) 4-1Isomer 2 6.3 (36) NT NT <4.7 (3) 5-1 Isomer 1 6.5 (131) 5.1 (17) <4.7(8) 6.6 (25) 5-1 Isomer 2 6.8 (77) <4.7 (14) <4.7 (6) <4.7 (8) 5-2Isomer 1 7.0 (78) <4.7 (3) <4.7 (9) 7.1 (37) 5-2 Isomer 2 7.0 (48) <4.7(3) <4.7 (4) 7.2 (20) 5-3 Mixture of 7.5 (80) <4.7 (7) 5.2 (19) 7.5 (37)isomers 5-4 Isomer 1 6.4 (76) NT NT <4.7 (39) 5-4 Isomer 2 6.8 (72) <4.7(2) <4.7 (0) <4.7 (8) 6-1 Isomer 1 5.6 (78) NT NT <4.7 (53) 6-1 Isomer 27.7 (104) <4.7 (18) <4.7 (5) 7.2 (33) 6-2 Isomer 2 8.7 (118) 7.8 (30)<4.7 (18) 8.4 (78) 6-3 Isomer 2 7.6 (112) 5.9 (24) <4.7 (48) 7.4 (81)7-1 Isomer 1 7.4 (46) <4.7 (1) <4.7 (2) <4.7 (5) 9-1 Isomer 2 8.4 (103)<4.7 (12) <4.7 (22) 8.6 (60) 9-2 Isomer 1 <4.7 (23) NT NT <4.7 (13) 9-2Isomer 2 <4.7 (18) NT NT <4.7 (8) 9-2 Isomer 3 6.3 (113) NT NT 7.1 (81)9-2 Isomer 4 8.0 (103) NT NT 8.3 (66) NT—not tested

Example B Passive Avoidance

Studies were carried out as described previously by Foley et al., (2004)Neuropsychopharmacology. In the passive avoidance task scopolamineadministration (1 mg/kg, i.p.) at 6 hours following training renderedanimals amnesic of the paradigm. A dose range of 3, 10, and 30 mg/kg(po) free base, administered 90 minutes prior to the training period viaoral gavage, was examined.

Example 2-2 Isomer 1 was found to reverse scopolamine-induced amnesia ofthe paradigm in a dose-dependent manner, with an approximate ED₅₀ of ca.10 mg/kg (po). The effect of 30 mg/kg was similar to that produced bythe cholinesterase inhibitor donepezil (0.1 mg/kg, ip) which served as apositive control (FIG. 1).

EQUIVALENTS

The foregoing examples are presented for the purpose of illustrating theinvention and should not be construed as imposing any limitation on thescope of the invention. It will readily be apparent that numerousmodifications and alterations may be made to the specific embodiments ofthe invention described above and illustrated in the examples withoutdeparting from the principles underlying the invention. All suchmodifications and alterations are intended to be embraced by thisapplication.

1. A compound which is selected from the group consisting of: ethyl5-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate;methyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;2-fluoroethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;prop-2-yn-1-yl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;but-2-yn-1-yl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;8-(8-butanoyl-8-azabicyclo[3.2.1]oct-3-yl)-2,8-diazaspiro[4.5]decan-3-one;ethyl3-(1-methyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(1-ethyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(3-oxo-1-propyl-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(1-benzyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl2-fluoro-3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(6-fluoro-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(2-ethyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(4-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-[2-oxo-4-(propan-2-yl)-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl2-fluoro-3-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;methyl3-(2-oxo-1,3,8-triazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(2-oxo-1,3,8-triazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(1-benzyl-3-oxo-1,2,8-triazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;Ethyl3-(2-oxo-4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;Ethyl(3-endo)-3-(2-hydroxy-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(3-oxo-2-propyl-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-[3-oxo-2-(propan-2-yl)-2,8-diazaspiro[4.5]dec-8-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-[2-(2-methylpropyl)-3-oxo-2,8-diazaspiro[4.5]dec-8-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-[2-(cyclopropylmethyl)-3-oxo-2,8-diazaspiro[4.5]dec-8-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-[2-(2-methoxyethyl)-3-oxo-2,8-diazaspiro[4.5]dec-8-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate;(1,1-²H₂)ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;(2,2,2-²H₃)ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;(²H₅)ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;propan-2-yl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;S-methyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carbothioate;S-ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carbothioate;ethyl5-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl5-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl5-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl5-[2-oxo-4-(2,2,2-trifluoroethyl)-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl5-(3-oxo-1-propyl-1,2,8-triazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl8-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.2.1]octane-3-carboxylate;ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate;prop-2-yn-1-yl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate;but-2-yn-1-yl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate;ethyl3-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate;methyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azabicyclo[3.2.1]octane-6-carboxylate;ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azabicyclo[3.2.1]octane-6-carboxylate;ethyl3-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azabicyclo[3.2.1]octane-6-carboxylate;ethyl6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.2.1]octane-3-carboxylate;ethyl6-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.1.1]heptane-3-carboxylate;ethyl3-(3-oxo-2,8-diazaspiro[4.6]undec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(2-oxo-1-oxa-3,8-diazaspiro[4.6]undec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;or a salt thereof.
 2. The compound according to claim 1 which isselected from the group consisting of: ethyl3-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(4-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-[2-oxo-4-(propan-2-yl)-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl2-fluoro-3-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;methyl3-(2-oxo-1,3,8-triazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(2-oxo-1,3,8-triazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(1-benzyl-3-oxo-1,2,8-triazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;Ethyl3-(2-oxo-4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;propan-2-yl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl5-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl5-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl5-[2-oxo-4-(2,2,2-trifluoroethyl)-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl5-(3-oxo-1-propyl-1,2,8-triazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl3-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate;ethyl3-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azabicyclo[3.2.1]octane-6-carboxylate;ethyl3-(3-oxo-2,8-diazaspiro[4.6]undec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-(2-oxo-1-oxa-3,8-diazaspiro[4.6]undec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;or a salt thereof.
 3. The compound according to claim 1 which is ethyl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,or a salt thereof.
 4. The compound according to claim 1 which isprop-2-yn-1-yl3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,or a salt thereof.
 5. The compound according to claim 1 which is ethyl(3-endo)-3-(2-hydroxy-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,or a salt thereof.
 6. The compound according to claim 1 which is ethyl5-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate,or a salt thereof.
 7. The compound according to claim 1 which is ethyl6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.2.1]octane-3-carboxylate,or a salt thereof.
 8. The compound according to claim 1 which is ethyl3-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,or a salt thereof.
 9. A pharmaceutical composition comprising a compoundas defined in claim 1 and a pharmaceutically acceptable excipient.
 10. Amethod of treating a cognitive disorder or psychotic disorder or for thetreatment or lessening the severity of acute, chronic, neuropathic, orinflammatory pain comprising administering an effective amount of acompound according to claim 1 to a subject in need thereof.
 11. Themethod according to claim 10, wherein the disorder is dementia.
 12. Themethod according to claim 10, wherein the disorder is dementia with Lewybodies.
 13. The method according to claim 10, wherein the disorder isAlzheimer's disease.
 14. The method according to claim 10, wherein thedisorder is Schizophrenia.